Fused Heteroaryl Derivatives for Use as P38 Kinase Inhibitors

ABSTRACT

Compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     are inhibitors of p38 kinase and are useful in the treatment of conditions or disease states mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38.

This invention relates to novel compounds and their use aspharmaceuticals, particularly as p38 kinase inhibitors, for thetreatment of conditions or disease states mediated by p38 kinaseactivity or mediated by cytokines produced by the activity of p38kinase.

We have now found a group of novel compounds that are inhibitors of p38kinase.

According to the invention there is provided a compound of formula (I):

wherein

A is a fused 5-membered heteroaryl ring substituted by —(CH₂)_(m)aryl or—(CH₂)_(m)heteroaryl wherein the aryl or heteroaryl is optionallysubstituted by one or more substituents independently selected from oxo,C₁₋₆alkyl, halogen, —CN, trifluoromethyl, —OR³, —(CH₂)_(n)CO₂R³, —NR³R⁴,—(CH₂)_(n)CONR³R⁴, —NHCOR³, —SO₂NR³R⁴, —NHSO₂R³ and —S(O)_(p)R³, and

A is optionally further substituted by one substituent selected from—OR⁵, halogen, trifluoromethyl, —CN, —CO₂R⁵ and C₁₋₆alkyl optionallysubstituted by hydroxy;

R¹ is selected from methyl and chloro;

R² is selected from —NH—CO—R⁶ and —CO—NH—(CH₂)_(q)—R⁷;

R³ is selected from hydrogen, —(CH₂)_(r)C₃₋₇cycloalkyl,—(CH₂)_(r)heterocyclyl, (CH₂)_(r)aryl, and C₁₋₆alkyl optionallysubstituted by up to two substituents independently selected from —OR⁸and —NR⁸R⁹,

R⁴ is selected from hydrogen and C₁₋₆alkyl, or

R³ and R⁴, together with the nitrogen atom to which they are bound, forma 5- or 6-membered heterocyclic ring optionally containing oneadditional heteroatoms elected from oxygen, sulfur and N—R¹⁰;

R⁵ is selected from hydrogen and C₁₋₆alkyl;

R⁶ is selected from hydrogen, C₁₋₆alkyl, —(CH₂)_(q)—C₃₋₇cycloalkyl,trifluoromethyl, —(CH₂)_(s)heteroaryl optionally substituted by R¹¹and/or R¹², and —(CH₂)_(s)phenyl optionally substituted by R¹¹ and/orR¹²;

R⁷ is selected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, —CONHR¹³,phenyl optionally substituted by R¹¹ and/or R¹², and heteroaryloptionally substituted by R¹¹ and/or R¹²;

R⁸ and R⁹ are each independently selected from hydrogen and C₁₋₆alkyl;

R¹⁰ is selected from hydrogen and methyl;

R¹¹ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyl,—CONR¹³R¹⁴, —NHCOR¹⁴, halogen, —CN, —(CH₂)_(t)NR¹⁵R¹⁶, trifluoromethyl,phenyl optionally substituted by one or more R¹² groups, and heteroaryloptionally substituted by one or more R¹² groups;

R¹² is selected from C₁₋₆alkyl, C₁₋₆alkoxy, halogen, trifluoromethyl,and —(CH₂)_(t)NR¹⁵R¹⁶;

R¹³ and R¹⁴ are each independently selected from hydrogen and C₁₋₆alkyl,or

R¹³ and R¹⁴, together with the nitrogen atom to which they are bound,form a 5- or 6-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and N—R¹⁰, whereinthe ring may be substituted by up to two C₁₋₆alkyl groups;

R¹⁵ is selected from hydrogen, C₁₋₆alkyl and —(CH₂)_(q)—C₃₋₇cycloalkyloptionally substituted by C₁₋₆alkyl,

R¹⁶ is selected from hydrogen and C₁₋₆alkyl, or

R¹⁵ and R¹⁶, together with the nitrogen atom to which they are bound,form a 5- or 6-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and N—R¹⁰;

X and Y are each independently selected from hydrogen, methyl andhalogen;

m, n, p and q are each independently selected from 0, 1 and 2;

r and s are each independently selected from 0 and 1; and

t is selected from 0, 1, 2 and 3;

with the proviso that when A is substituted by —(CH₂)_(m)heteroaryl andm is 0, the —(CH₂)_(m)heteroaryl group is not a 5-membered heteroarylring optionally substituted by C₁₋₂alkyl;

or a pharmaceutically acceptable derivative thereof.

In one embodiment, A includes fused 5-membered heteroaryl ringscontaining up to two heteroatoms independently selected from oxygen,nitrogen and sulfur. In another embodiment, A includes fused 5-memberedheteroaryl rings containing up to two heteroatoms independently selectedfrom oxygen and nitrogen. In a further embodiment, A includes 5-memberedheteroaryl rings containing two heteroatoms independently selected fromoxygen and nitrogen, for example rings containing a nitrogen atom andone additional heteroatom selected from oxygen and nitrogen. Examples ofsuitable A groups include fused isoxazolyl, pyrazolyl, pyrrolyl andthiazolyl rings such as those shown below:

Representative examples of A groups include fused isoxazolyl, pyrazolyland pyrrolyl rings such as those shown below:

For example, A may be a fused pyrazolyl ring such as those shown below:

A representative example of a compound of formula (I) is wherein ring Ais substituted by —(CH₂)_(m)aryl or —(CH₂)_(m)heteroaryl, located on anyposition on the ring.

For example, compounds of formula (I) include compounds wherein ring Ais substituted by —(CH₂)_(m)aryl or —(CH₂)_(m)heteroaryl located inposition (i), (ii), (iii) or (iv), for example position (ii) or (iii),as shown below:

In one embodiment, the —(CH₂)_(m)aryl group is —(CH₂)_(m)phenyl.

In one embodiment, the —(CH₂)_(m)heteroaryl group is a group wherein theheteroaryl is a 5- or 6-membered heteroaryl ring containing up to twoheteroatoms independently selected from oxygen, nitrogen and sulfur. Ina further embodiment, the —(CH₂)_(m)heteroaryl group include groupswherein the heteroaryl is a 5- or 6-membered heteroaryl ring containingup to two heteroatoms independently selected from oxygen and nitrogen,for example pyridyl, isoxazolyl, pyrazolyl, imidazolyl, pyrimidinyl orpyrazinyl. Representative examples of the —(CH₂)_(m)heteroaryl groupinclude groups wherein the heteroaryl is a 5- or 6-membered heteroarylring containing up to two heteroatoms independently selected from oxygenand nitrogen, for example pyridyl, isoxazolyl or pyrimidinyl. Furtherrepresentative examples of the —(CH₂)_(m)heteroaryl group include groupswherein the heteroaryl is a 5- or 6-membered heteroaryl ring containingup to two heteroatoms independently selected from oxygen and nitrogen,for example pyrazolyl, imidazolyl or pyrazinyl.

The —(CH₂)_(m)aryl and —(CH₂)_(m)heteroaryl groups are optionallysubstituted and the substituents may be located on any position on thearyl or heteroaryl.

In one embodiment, the aryl or heteroaryl is optionally substituted byone or two substituents independently selected from oxo, C₁₋₆alkyl,halogen, —CN, trifluoromethyl, —OR³, —(CH₂)_(n)CO₂R³, —NR³R⁴,—(CH₂)_(n)CONR³R⁴, —NHCOR³, —SO₂NR³R⁴, —NHSO₂R³ and —S(O)_(p)R³. Inanother embodiment, the aryl is optionally substituted by one or twosubstituents independently selected from C₁₋₆alkyl, halogen, —CN,trifluoromethyl, —OR³, —NR³R⁴, —(CH₂)_(n)CONR³R⁴ and —S(O)_(p)R³.Representative examples of substituents for the aryl include one or twosubstituents independently selected from C₁₋₆alkyl, in particularmethyl, halogen, —CN, trifluoromethyl, —OR³, —NR³R⁴, —(CH₂)_(n)CONR³R⁴and —S(O)_(p)R³. For example, aryl is optionally substituted by halogen,in particular fluorine, —OR³, in particular methoxy, or—(CH₂)_(n)CONR³R⁴. In a further embodiment, the heteroaryl is optionallysubstituted by one or two substituents independently selected from oxo,C₁₋₆alkyl, halogen, —OR³, —NR³R⁴ and —(CH₂)_(n)CONR³R⁴. Representativeexamples of substituents for the heteroaryl include one or twosubstituents independently selected from oxo and C₁₋₆alkyl, inparticular methyl. Further representative examples of substituents forthe heteroaryl include one or two substituents independently selectedfrom halogen, —OR³, —NR³R⁴ and —(CH₂)_(n)CONR³R⁴.

A representative example of R¹ is methyl.

A representative example of R² is —CO_NH—(CH₂)_(q)—R⁷.

Representative examples of R³ include hydrogen;—(CH₂)_(r)C₃₋₇cycloalkyl, in particular —(CH₂)_(r)cyclohexyl;—(CH₂)_(r)heterocyclyl, in particular wherein the heterocyclyl is a 5-or 6-membered heterocyclyl containing one heteroatom selected fromoxygen, nitrogen and sulfur such a tetrahydrofuran or tetrahydropyran;and C₁₋₆alkyl, in particular C₁₋₄alkyl such as methyl, ethyl, orn-propyl, optionally substituted by up to two substituents independentlyselected from —OR⁸ and —NR⁸R⁹.

A representative example of R⁴ is hydrogen.

Alternatively, R³ and R⁴, together with the nitrogen atom to which theyare bound, form a 5- or 6-membered heterocyclic ring optionallycontaining one additional heteroatom selected from oxygen, sulfur andN—R¹⁰, in particular morpholinyl.

In one embodiment, R⁵ is selected from hydrogen and C₁₋₄alkyl.

In one embodiment, R⁶ is a —(CH₂)_(s)heteroaryl optionally substitutedby R¹¹ and/or R¹².

Representative examples of R⁷ include hydrogen; C₁₋₆alkyl, in particularC₁₋₄alkyl such as methyl, ethyl, n-propyl, isopropyl and n-butyl;C₃₋₇cycloalkyl, in particular C₃₋₆cycloalkyl such as cyclopropyl,cyclobutyl and cyclopentyl; phenyl optionally substituted by R¹¹ and/orR¹²; and heteroaryl, in particular a 5- or 6-membered heteroarylcontaining two heteroatoms selected from nitrogen and oxygen, forexample pyrazolyl, pyridazinyl and pyrimidinyl, optionally substitutedby R¹¹ and/or R¹².

Representative examples of R⁸ and R⁹ include hydrogen and C₁₋₄alkyl, inparticular hydrogen and methyl.

In one embodiment, R¹¹ is selected from C₁₋₆alkyl, in particularC₁₋₄alkyl such as methyl or ethyl, or halogen, in particular fluorine.

In one embodiment, R¹² is selected from C₁₋₆alkyl, in particularC₁₋₄alkyl such as methyl or ethyl, or halogen, in particular fluorine.

A representative example of R¹¹ and R¹² is halogen, in particularfluorine. A further representative example of R¹¹ and R¹² is C₁₋₄alkylsuch as methyl or ethyl.

In one embodiment, R¹³ and R¹⁴ are each independently hydrogen orC₁₋₄alkyl.

In one embodiment, R¹⁵ and R¹⁶, together with the nitrogen atom to whichthey are bound, form a 5- or 6-membered heterocyclic ring optionallyfurther containing one additional oxygen atom.

In one embodiment, X and Y are each independently selected fromhydrogen, chlorine and fluorine. Representative examples of X includehydrogen and fluorine. A representative example of Y is hydrogen.

In one embodiment, when A is a fused 5-membered heteroaryl ringsubstituted by —(CH₂)_(m)aryl and m is 0, 1 or 2, or A is a fused5-membered heteroaryl ring substituted by —(CH₂)_(m)heteroaryl and m is1 or 2, the aryl or heteroaryl is optionally substituted by one or moresubstituents independently selected from oxo, C₁₋₆alkyl, halogen, —CN,trifluoromethyl, —OR³, —(CH₂)_(n)CO₂R³, —NR³R⁴, —(CH₂)_(n)CONR³R⁴,—NHCOR³, —SO₂NR³R⁴, —NHSO₂R³ and —S(O)_(p)R³, and, when A is a fused5-membered heteroaryl ring substituted by —(CH₂)_(m)heteroaryl and m is0, the heteroaryl is a 5-membered heteroaryl ring substituted by one ormore substituents independently selected from oxo, C₃₋₆alkyl, halogen,—CN, trifluoromethyl, —OR³, —(CH₂)_(n)CO₂R³, —NR³R⁴, —(CH₂)_(n)CONR³R⁴,—NHCOR³, —SO₂NR³R⁴, —NHSO₂R³ and —S(O)_(p)R³, the heteroaryl is a5-membered heteroaryl ring substituted by C₁₋₂alkyl and one or moresubstituents independently selected from oxo, C₁₋₆alkyl, halogen, —CN,trifluoromethyl, —OR³, —(CH₂)_(n)CO₂R³, —NR³R⁴, —(CH₂)_(n)CONR³R⁴,—NHCOR³, —SO₂NR³R⁴, —NHSO₂R³ and —S(O)_(p)R³, or the heteroaryl is a6-membered heteroaryl ring optionally substituted by one or moresubstituents independently selected from oxo, C₁₋₆alkyl, halogen, —CN,trifluoromethyl, —OR³, —(CH₂)_(n)CO₂R³, —NR³R⁴, —(CH₂)_(n)CONR³R⁴,—NHCOR³, —SO₂NR³R⁴, —NHSO₂R³ and —S(O)_(p)R³.

Representative examples of m include 0 and 1.

In one embodiment, n is selected from 0 and 1. A representative exampleof n is 1. A further representative example of n is 0.

A representative example of p is 2.

Representative examples of q include 0 and 1.

Representative examples of r include 0 and 1.

In one embodiment, s is 0.

In one embodiment, t is 0.

It is to be understood that the present invention covers allcombinations of the embodiments and the particular and preferred groupsdescribed hereinabove. It is also to be understood that the presentinvention encompasses compounds of formula (I) in which a particulargroup or parameter, for example R³, R⁴, R⁸, R⁹, R¹⁰, R¹², R¹⁵, R¹⁶, n,p, q, r or t, may occur more than once. In such compounds it will beappreciated that each group or parameter is independently selected fromthe values listed.

Particular compounds according to the invention include those mentionedin the Examples. Specific examples which may be mentioned include

-   N-cyclopropyl-3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide;-   N-cyclopropyl-3-fluoro-5-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methylbenzamide;-   N-cyclopropyl-3-fluoro-5-[1-(4-fluoro-2-methylphenyl)-1H-indazol-5-yl]-4-methylbenzamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-{1-[4-(4-morpholinyl)phenyl]-1H-indazol-5-yl}benzamide;-   N-ethyl-3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide;-   N-(cyclopropylmethyl)-3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-{1-[4-(methylsulfonyl)phenyl]-1H-indazol-5-yl}benzamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-(1-{4-[2-(methylamino)-2-oxoethyl]phenyl}-1H-indazol-5-yl)benzamide;-   N-cyclopropyl-3-[1-(4-{[2-(dimethylamino)ethyl]amino}phenyl)-1H-indazol-5-yl]-5-fluoro-4-methylbenzamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-{1-[4-(tetrahydro-2H-pyran-4-ylamino)phenyl]-1H-indazol-5-yl}benzamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-(1-{4-[(tetrahydro-2-furanylmethyl)amino]phenyl}-1H-indazol-5-yl)benzamide;-   N-cyclopropyl-3-(1-{4-[(2,3-dihydroxypropyl)amino]phenyl}-1H-indazol-5-yl)-5-fluoro-4-methylbenzamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-{3-[4-(methyloxy)phenyl]-1,2-benzisoxazol-6-yl}benzamide;-   N-cyclopropyl-3-fluoro-5-[3-(4-hydroxyphenyl)-1,2-benzisoxazol-6-yl]-4-methylbenzamide;-   N-cyclopropyl-3-fluoro-4-methyl-5-{1-[(1-oxido-2-pyridinyl)methyl]-1H-indazol-5-yl}benzamide;-   N-ethyl-3-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide;-   N-cyclopropyl-3-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide;-   N-ethyl-4-methyl-3-{3-[4-(methyloxy)phenyl]-1H-indazol-6-yl}benzamide;    and-   N-cyclopropyl-4-methyl-3-{3-[4-(methyloxy)phenyl]-1H-indazol-6-yl}benzamide;    and pharmaceutically acceptable derivatives thereof.

Further specific examples which may be mentioned include:

-   N-(1-ethyl-1H-pyrazol-5-yl)-3-fluoro-5-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide;-   3-fluoro-5-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide;-   N-ethyl-3-fluoro-5-{3-[4-fluoro-2-(methyloxy)phenyl]-1H-indazol-6-yl}-4-methylbenzamide;-   N-(1,4-dimethyl-1H-pyrazol-5-yl)-3-fluoro-5-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide;    and-   N-(1,4-dimethyl-1H-pyrazol-5-yl)-3-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide;    and pharmaceutically acceptable derivatives thereof.

As used herein, the term “pharmaceutically acceptable” means a compoundwhich is suitable for pharmaceutical use. Salts and solvates ofcompounds of the invention which are suitable for use in medicine arethose wherein the counterion or associated solvent is pharmaceuticallyacceptable. However, salts and solvates having non-pharmaceuticallyacceptable counterions or associated solvents are within the scope ofthe present invention, for example, for use as intermediates in thepreparation of other compounds of the invention and theirpharmaceutically acceptable salts and solvates.

As used herein, the term “pharmaceutically acceptable derivative”, meansany pharmaceutically acceptable salt, solvate or prodrug, e.g. ester, ofa compound of the invention, which upon administration to the recipientis capable of providing (directly or indirectly) a compound of theinvention, or an active metabolite or residue thereof. Such derivativesare recognizable to those skilled in the art, without undueexperimentation. Nevertheless, reference is made to the teaching ofBurger's Medicinal Chemistry and Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent of teaching such derivatives. Preferred pharmaceuticallyacceptable derivatives are salts, solvates, esters, carbamates andphosphate esters. Particularly preferred pharmaceutically acceptablederivatives are salts, solvates and esters. Most preferredpharmaceutically acceptable derivatives are salts and esters, inparticular salts.

The compounds of the present invention may be in the form of and/or maybe administered as a pharmaceutically acceptable salt. For a review onsuitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19.

Typically, a pharmaceutical acceptable salt may be readily prepared byusing a desired acid or base as appropriate. The salt may precipitatefrom solution and be collected by filtration or may be recovered byevaporation of the solvent.

Salts of the compounds of the present invention may, for example,comprise acid addition salts resulting from reaction of an acid with anitrogen atom present in a compound of formula (I). Salts encompassedwithin the term “pharmaceutically acceptable salts” refer to non-toxicsalts of the compounds of this invention. Suitable addition salts areformed from acids which form non-toxic salts and examples are acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,ethanesulfonate, formate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydrogen phosphate, hydroiodide, hydroxynaphthoate,iodide, isethionate, lactate, lactobionate, laurate, malate, maleate,mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine,oxalate, oxaloacetate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, piruvate, polygalacturonate, saccharate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate, triethiodide, trifluoroacetate and valerate.Representative salts include formate salts such as the mono- anddi-formate salts.

Pharmaceutically acceptable base salts include ammonium salts such as atrimethylammonium salt, alkali metal salts such as those of sodium andpotassium, alkaline earth metal salts such as those of calcium andmagnesium and salts with organic bases, including salts of primary,secondary and tertiary amines, such as isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexyl amine andN-methyl-D-glucamine.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. As used herein, the term “solvate”refers to a complex of variable stoichiometry formed by a solute (inthis invention, a compound of formula (I) or a salt thereof) and asolvent. Such solvents for the purpose of the invention may notinterfere with the biological activity of the solute. Examples ofsuitable solvents include water, methanol, ethanol and acetic acid.Preferably the solvent used is a pharmaceutically acceptable solvent.Examples of suitable pharmaceutically acceptable solvents include water,ethanol and acetic acid. Most preferably the solvent used is water. Acomplex with water is known as a “hydrate”. Solvates of the compounds ofthe invention are within the scope of the invention.

As used herein, the term “prodrug” means a compound which is convertedwithin the body, e.g. by hydrolysis in the blood, into its active formthat has medical effects. Pharmaceutically acceptable prodrugs aredescribed in T. Higuchi and V. Stella, Prodrugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series; Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987; and in D. Fleisher, S. Ramon andH. Barbra “Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19(2)115-130, each of which are incorporated herein by reference.

Prodrugs are any covalently bonded carriers that release a compound offormula (I) in vivo when such prodrug is administered to a patient.Prodrugs are generally prepared by modifying functional groups in a waysuch that the modification is cleaved, either by routine manipulation orin vivo, yielding the parent compound. Prodrugs include, for example,compounds of this invention wherein hydroxy or amine groups are bondedto any group that, when administered to a patient, cleaves to form thehydroxy or amine groups. Thus, representative examples of prodrugsinclude (but are not limited to) acetate, formate and benzoatederivatives of alcohol and amine functional groups of the compounds offormula (I). Further, in the case of a carboxylic acid (—COOH), estersmay be employed, such as methyl esters, ethyl esters, and the like.Esters may be active in their own right and/or be hydrolysable under invivo conditions in the human body. Suitable pharmaceutically acceptablein vivo hydrolysable ester groups include those which break down readilyin the human body to leave the parent acid or its salt.

As used herein, the term “alkyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms. Forexample, C₁₋₆alkyl means a straight or branched alkyl containing atleast 1, and at most 6, carbon atoms. Examples of “alkyl” as used hereininclude, but are not limited to, methyl, ethyl, n-propyl, n-butyl,n-pentyl, isobutyl, isopropyl and t-butyl. A C₁₋₄alkyl group ispreferred, for example methyl, ethyl, isopropyl or t-butyl. The saidalkyl groups may be optionally substituted with one or more fluorineatoms for example, trifluoromethyl.

As used herein, the term “alkoxy” refers to a straight or branched chainalkoxy groups containing the specified number of carbon atoms. Forexample, C₁₋₆alkoxy means a straight or branched alkoxy containing atleast 1, and at most 6, carbon atoms. Examples of “alkoxy” as usedherein include, but are not limited to methoxy, ethoxy, propoxy,prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy,pentoxy, or hexyloxy. A C₁₋₄alkoxy group is preferred, for examplemethoxy or ethoxy.

As used herein, the term “cycloalkyl” refers to a non-aromatichydrocarbon ring containing the specified number of carbon atoms whichmay optionally contain up to one double bond. For example,C₃₋₇cycloalkyl means a non-aromatic ring containing at least three, andat most seven, ring carbon atoms. Examples of “cycloalkyl” as usedherein include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. A C₃₋₆cycloalkyl group ispreferred, for example, cyclopropyl, cyclopentyl or cyclohexyl.

As used herein, the term “aryl” refers to an aromatic carbocyclic ringsuch as phenyl, biphenyl or naphthyl. Preferably the aryl is phenyl.

As used herein, the terms “heteroaryl ring” and “heteroaryl”, unlessotherwise defined, refer to a monocyclic 5- to 7-membered unsaturatedhydrocarbon ring containing at least one heteroatom independentlyselected from oxygen, nitrogen and sulfur. Preferably, the heteroarylring has five or six ring atoms. Examples of heteroaryl rings include,but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyland triazinyl. The said ring may be optionally substituted by one ormore substituents independently selected from C₁₋₆alkyl and oxy.

As used herein, the terms “heterocyclic ring” or “heterocyclyl”, unlessotherwise defined refer to a monocyclic 3- to 7-membered saturatedhydrocarbon ring containing at least one heteroatom independentlyselected from oxygen, nitrogen and sulfur. Preferably, the heterocyclylring has five or six ring atoms. Examples of heterocyclyl groupsinclude, but are not limited to, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidyl, piperazinyl, morpholino, tetrahydropyranyl,tetrahydrofuranyl, and thiomorpholino. The said ring may be optionallysubstituted by one or more substituents independently selected fromC₁₋₆alkyl and oxy.

As used herein, the terms “halogen” or “halo” refer to the elementsfluorine, chlorine, bromine and iodine. Preferred halogens are fluorine,chlorine and bromine. A particularly preferred halogen is fluorine orchlorine.

As used herein, the terms “halogen” or “halo” refer to the elementsfluorine, chlorine, bromine and iodine. Preferred halogens are fluorine,chlorine and bromine. A particularly preferred halogen is fluorine orchlorine.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibitcis-trans isomerism). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe present invention. The present invention also covers the individualisomers of the compounds represented by formula (I) as mixtures withisomers thereof in which one or more chiral centres are inverted.Likewise, it is understood that compounds of formula (I) may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention.

Separation of diastereoisomers or cis and trans isomers may be achievedby conventional techniques, e.g. by fractional crystallisation,chromatography or H.P.L.C. A stereoisomeric mixture of the agent mayalso be prepared from a corresponding optically pure intermediate or byresolution, such as H.P.L.C. of the corresponding racemate using asuitable chiral support or by fractional crystallisation of thediastereoisomeric salts formed by reaction of the corresponding racematewith a suitable optically active acid or base, as appropriate.

Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention.

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the workingExamples.

A compound of formula (I) may be prepared by reacting a compound offormula (II)

in which R¹, R², X and Y are as hereinbefore defined and A¹ is anunsubstituted fused 5-membered heteroaryl ring, with a suitable reagent,for example a halide derivative of formula (IIIA) or (IIIB)

Z-(CH₂)_(m)aryl  (IIIA)

Z-(CH₂)_(m)heteroaryl  (IIIB)

in which —(CH₂)_(m)aryl and —(CH₂)_(m)heteroaryl are as hereinbeforedefined and Z is halogen, in particular bromine,in, for example, the presence of a base such as sodium hydride and asolvent such as DMF.

Alternatively, when A is substituted by —(CH₂)_(m)aryl wherein m is 0,the compound of formula (II) may be reacted with a boronic acid compoundof formula (IV)

(HO)₂B—(CH₂)_(m)aryl  (IV)

in which —(CH₂)_(m)aryl is as hereinbefore defined,in the presence of copper (I) acetate and pyridine.

A compound of formula (I) or a compound of formula (II) may be preparedby reacting a compound of formula (V)

in which A² is A as hereinbefore defined, in which case the resultingproduct is a compound of formula (I), A² is A¹ as hereinbefore defined,in which case the resulting product is a compound of formula (II), or A²is a protected form of A or A¹, and Z¹ is halogen, in particularbromine,with a compound of formula (VIA) or (VIB)

in which R¹, R², X and Y are as hereinbefore defined,in the presence of a catalyst, for exampletetrakis(triphenylphosphine)palladium,and, if necessary, removing any protecting groups.

A compound of formula (V) wherein A² is A and A is a fused pyrazolylring may, for example, be prepared by reacting a compound of formula(VII)

in which Z¹ is as hereinbefore defined and Z² is halogen, in particularfluorine,with a hydrazine derivative of formula (VIIIA) or (VIIIB)

H₂NNH—(CH₂)_(m)aryl  (VIIIA)

H₂NNH—(CH₂)_(m)heteroaryl  (VIIIB)

in which —(CH₂)_(m)aryl and —(CH₂)_(m)heteroaryl are as hereinbeforedefined,followed by cyclisation in the presence of a base such as DBU.

Alternatively, a compound of formula (V) wherein A² is A and A is afused pyrazolyl ring may, for example, be prepared by reacting acompound of formula (IX)

in which Z¹, Z², —(CH₂)_(m)aryl and —(CH₂)_(m)heteroaryl are ashereinbefore defined,with a protected hydrazine derivative of formula (X)

H₂NNH—P  (X)

in which P is a protecting group such as Boc,followed by cyclisation in the presence of a base such as DBU.

A compound of formula (V) wherein A² is A and A is a fused isoxazolylring may, for example, be prepared by reacting a compound of formula(IX) as hereinbefore defined with hydroxylamine, followed by cyclisationin the presence of a base such as DBU.

A compound of formula (VIA) may be prepared by, for example, reacting acompound of formula (XI)

in which R¹, R², X and Y are as hereinbefore defined and Z³ is halogen,in particular iodine, with bis(pinacolato)diboron,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex(PdCl₂(ppdf)) and potassium acetate in a solvent such as DMF.

A compound of formula (VIB) may be prepared by, for example, reacting acompound of formula (XI) as hereinbefore defined, with n-butyl lithiumand triisopropyl borate in a solvent such as THF.

When R² is —NH—CO—R⁶, a compound of formula (XI) may be prepared byreacting an amine of formula (XII)

in which R¹, X, Y and Z³ are as hereinbefore defined,with an acid compound of formula (XIII)

R⁶CO₂H  (XIII)

in which R⁶ is as hereinbefore defined,under amide forming conditions.

Suitable amide forming conditions are well known in the art and includeadding a base such as DIPEA to a mixture of the amine of formula (XII),the acid of formula (XIII), and HATU in a solvent such as DMF.

Alternatively, when R² is —CO—NH—(CH₂)_(q)—R⁷, a compound of formula(XI) may readily be prepared from a corresponding acid compound offormula (XIV)

in which R¹, X, Y and Z³ are as hereinbefore defined,by converting the acid to an activated form of the acid, for example theacid chloride, by treatment with, for example, thionyl chloride, andthen reacting the activated acid thus formed with an amine compound offormula (XV)

R⁷—(CH₂)_(q)—NH₂  (XV)

in which R⁷ is as hereinbefore defined,under amide forming conditions.

Suitable amide forming conditions are well known in the art and includetreating a solution of the acid of formula (XIV), or the activated formthereof, in for example DMF, with an amine of formula (XV) in thepresence of a base such as triethylamine.

Alternatively, when R² is —CO—NH—(CH₂)_(q)—R⁷, a compound of formula (I)may be prepared from a corresponding acid compound of formula (XVI)

in which A, R¹, X and Y are as hereinbefore defined,by reacting the acid with an amine compound of formula (XV) ashereinbefore defined under the conditions described above.

When A is a fused pyrazolyl, another general method for preparingcompounds of formula (I) comprises reacting a compound of formula (XVII)

in which R¹, R², X, Y and Z³ are as hereinbefore defined, with ahydrazine derivative of formula (VIIIA) or (VIIIB) as hereinbeforedefined.

A compound of formula (I) may also be prepared by reacting a compound offormula (XVIII)

in which R¹, R², X and Y are as hereinbefore defined and A³ is a fused5-membered heteroaryl ring substituted by halogen, with a suitableboronic acid derivative.

Alternatively, a further general method comprises final stagemodification of one compound of formula (I) into another compound offormula (I). Suitable functional group transformations for convertingone compound of formula (I) into another compound of formula (I) arewell known in the art and are described in, for instance, ComprehensiveHeterocyclic Chemistry II, eds. A. R. Katritzky, C. W. Rees and E. F. V.Scriven (Pergamon Press, 1996), Comprehensive Organic Functional GroupTransformations, eds. A. R. Katritzky, O. Meth-Cohn and C. W. Rees(Elsevier Science Ltd., Oxford, 1995), Comprehensive Organic Chemistry,eds. D. Barton and W. D. Ollis (Pergamon Press, Oxford, 1979), andComprehensive Organic Transformations, R. C. Larock (VCH PublishersInc., New York, 1989).

For example, one general method for preparing the compounds of formula(I) comprises the reaction set out in Scheme 1 below.

For example, another general method for preparing the compounds offormula (I) comprises the reactions set out in Scheme 2 below.

For example, another method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 3 below.

For example, another method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 4 below.

For example, another method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 5 below.

For example, another method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 6 below.

For example, a further method for preparing the compounds of formula (I)comprises the reactions set out in Scheme 7 below.

Those skilled in the art will appreciate that in the preparation of thecompounds of the invention it may be necessary and/or desirable toprotect one or more sensitive groups in the molecule to preventundesirable side reactions. Suitable protecting groups for use accordingto the present invention are well known to those skilled in the art andmay be used in a conventional manner. See, for example, “Protectivegroups in organic synthesis” by T. W. Greene and P. G. M. Wuts (JohnWiley & sons 1991) or “Protecting Groups” by P. J. Kocienski (GeorgThieme Verlag 1994). Examples of suitable amino protecting groupsinclude acyl type protecting groups (e.g. formyl, trifluoroacetyl,acetyl), aromatic urethane type protecting groups (e.g.benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethaneprotecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc),t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl)and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).Examples of suitable oxygen protecting groups may include for examplealkyl silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl;alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such asacetate.

Whilst it is possible for the compounds of the present invention to beadministered as the raw chemical, the compounds of formula (I) and theirpharmaceutically acceptable derivatives are conveniently administered inthe form of pharmaceutical compositions eg when the agent is inadmixture with a suitable pharmaceutical excipient, diluent and/orcarrier selected with regard to the intended route of administration andstandard pharmaceutical practice.

Thus, in another aspect of the invention, we provide a pharmaceuticalcomposition comprising at least one compound of formula (I) or apharmaceutically acceptable derivative thereof, in association with oneor more pharmaceutically acceptable excipients, diluents and/orcarriers. The excipient, diluent or carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not deletrious to the recipient thereof.

According to a further aspect, the invention provides a pharmaceuticalcomposition comprising, as active ingredient, at least one compound ofthe invention or a pharmaceutically acceptable derivative thereof, inassociation one or more pharmaceutically acceptable excipients, diluentsand/or carriers for use in therapy, and in particular in the treatmentof human or animal subjects suffering from a condition susceptible toamelioration by an inhibitor of p38 kinase.

The present invention also provides a pharmaceutical compositioncomprising a therapeutically effective amount of the compounds of thepresent invention and a pharmaceutically acceptable excipient, diluentand/or carrier (including combinations thereof).

There is further provided by the present invention a process ofpreparing a pharmaceutical composition, which process comprises mixingat least one compound of the invention or a pharmaceutically acceptablederivative thereof, together with a pharmaceutically acceptableexcipient, diluent and/or carrier.

The pharmaceutical compositions may be for human or animal usage inhuman and veterinary medicine and will typically comprise any one ormore of a pharmaceutically acceptable excipient, diluent or carrier.Acceptable carriers or diluents for therapeutic use are well known inthe pharmaceutical art, and are described, for example, in Remington'sPharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).The choice of pharmaceutical excipient, diluent or carrier can beselected with regard to the intended route of administration andstandard pharmaceutical practice. The pharmaceutical compositions maycomprise as—or in addition to—the excipient, diluent or carrier anysuitable binder(s), lubricant(s), suspending agent(s), coating agent(s)and solubilising agent(s).

Preservatives, stabilisers, dyes and even flavouring agents may beprovided in the pharmaceutical composition. Examples of preservativesinclude sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid. Antioxidants and suspending agents may be also used.

For some embodiments, the agents of the present invention may also beused in combination with a cyclodextrin. Cyclodextrins are known to forminclusion and non-inclusion complexes with drug molecules. Formation ofa drug-cyclodextrin complex may modify the solubility, dissolution rate,bioavailability and/or stability property of a drug molecule.Drug-cyclodextrin complexes are generally useful for most dosage formsand administration routes. As an alternative to direct complexation withthe drug the cyclodextrin may be used as an auxiliary additive, e.g. asa carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrinsare most commonly used and suitable examples are described in WO91/11172, WO 94/02518 and WO 98/55148.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention may beprepared by processes known in the art, for example see WO 02/00196(SmithKline Beecham).

There may be different composition/formulation requirements dependent onthe different delivery systems. By way of example, the pharmaceuticalcomposition of the present invention may be formulated to be deliveredusing a mini-pump or by a mucosal route, for example, as a nasal sprayor aerosol for inhalation or ingestable solution, or parenterally inwhich the composition is formulated by an injectable form, for delivery,by, for example, an intravenous, intramuscular or subcutaneous route.Alternatively, the formulation may be designed to be delivered by bothroutes.

Where the agent is to be delivered mucosally through thegastrointestinal mucosa, it should be able to remain stable duringtransit though the gastrointestinal tract; for example, it should beresistant to proteolytic degradation, stable at acid pH and resistant tothe detergent effects of bile.

Where appropriate, the pharmaceutical compositions can be administeredby inhalation, in the form of a suppository or pessary, topically in theform of a lotion, solution, cream, ointment or dusting powder, by use ofa skin patch, orally in the form of tablets containing excipients suchas starch or lactose, or in capsules or ovules either alone or inadmixture with excipients, or in the form of elixirs, solutions orsuspensions containing flavouring or colouring agents, or they can beinjected parenterally, for example intravenously, intramuscularly orsubcutaneously. For parenteral administration, the compositions may bebest used in the form of a sterile aqueous solution which may containother substances, for example enough salts or monosaccharides to makethe solution isotonic with blood. For buccal or sublingualadministration the compositions may be administered in the form oftablets or lozenges which can be formulated in a conventional manner.

The routes for administration (delivery) include, but are not limitedto, one or more of: oral (e.g. as a tablet, capsule, or as an ingestablesolution), topical, mucosal (e.g. as a nasal spray or aerosol forinhalation), nasal, parenteral (e.g. by an injectable form),gastrointestinal, intraspinal, intraperitoneal, intramuscular,intravenous, intrauterine, intraocular, intradermal, intracranial,intratracheal, intravaginal, intracerebroventricular, intracerebral,subcutaneous, ophthalmic (including intravitreal or intracameral),transdermal, rectal, buccal, epidural and sublingual. It is to beunderstood that not all of the compounds need be administered by thesame route. Likewise, if the composition comprises more than one activecomponent, then those components may be administered by differentroutes.

The compounds of formula (I) and their pharmaceutically acceptable saltsand solvates may be formulated for administration in any suitablemanner. They may, for example, be formulated for topical administrationor administration by inhalation or, more preferably, for oral,transdermal or parenteral administration. The pharmaceutical compositionmay be in a form such that it can effect controlled release of thecompounds of formula (I) and their pharmaceutically acceptablederivatives. In a preferred embodiment, the agents of the presentinvention are delivered systemically such as orally, buccally orsublingually. A particularly preferred method of administration, andcorresponding formulation, is oral administration.

For oral administration, the pharmaceutical composition may take theform of, and be administered as, for example, tablets (includingsub-lingual tablets) and capsules (each including timed release andsustained release formulations), ovules, pills, powders, granules,elixirs, tinctures, emulsions, solutions, syrups or suspensions preparedby conventional means with acceptable excipients for immediate-,delayed-, modified-, sustained-, pulsed- or controlled-releaseapplications.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. The tablets may also contain excipientssuch as microcrystalline cellulose, lactose, sodium citrate, calciumcarbonate, dibasic calcium phosphate and glycine, disintegrants such asstarch (preferably corn, potato or tapioca starch), sodium starchglycollate, croscarmellose sodium and certain complex silicates, andgranulation binders such as polyvinylpyrrolidone,hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnesium stearate, stearic acid, glyceryl behenate and talc may beincluded.

Solid compositions of a similar type may also be employed as fillers ingelatin capsules. Preferred excipients in this regard include lactose,starch, a cellulose, milk sugar or high molecular weight polyethyleneglycols. For aqueous suspensions and/or elixirs, the agent may becombined with various sweetening or flavouring agents, colouring matteror dyes, with emulsifying and/or suspending agents and with diluentssuch as water, ethanol, propylene glycol and glycerin, and combinationsthereof.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate, as, for example, starch or mannitol. Flavoring,preservative, dispersing and coloring agent can also be present.

Capsules can be made by preparing a powder mixture as described above,and filling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additives suchas peppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

The compounds of the present invention can also be administered in theform of liposome emulsion delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The present invention includes pharmaceutical compositions containing0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula(I) in combination with a pharmaceutically acceptable carrier.

Likewise, the composition may also be administered in nasal, ophthalmic,otic, rectal, topical, intravenous (both bolus and infusion),intraperitoneal, intraarticular, subcutaneous or intramuscular,inhalation or insufflation form, all using forms well known to those ofordinary skill in the pharmaceutical arts.

For transdermal administration, the pharmaceutical composition may begiven in the form of a transdermal patch, such as a transdermaliontophoretic patch.

If the compound of the present invention is administered parenterally,then examples of such administration include one or more of:intravenously, intraarterially, intraperitoneally, intrathecally,intraventricularly, intraurethrally, intrasternally, intracranially,intramuscularly or subcutaneously administering the agent; and/or byusing infusion techniques. For parenteral administration, thepharmaceutical composition may be given as an injection or a continuousinfusion (e.g. intravenously, intravascularly or subcutaneously). Thecompositions may take such forms as suspensions, solutions or emulsionsin oily or aqueous vehicles and may contain formulatory a gents such assuspending, stabilizing and/or dispersing agents. For administration byinjection these may take the form of a unit dose presentation or as amultidose presentation preferably with an added preservative.Alternatively for parenteral administration the active ingredient may bein powder form for reconstitution with a suitable vehicle. Forparenteral administration, the compound is best used in the form of asterile aqueous solution which may contain other substances, forexample, enough salts or glucose to make the solution isotonic withblood. The aqueous solutions should be suitably buffered (preferably toa pH of from 3 to 9), if necessary. The preparation of suitableparenteral formulations under sterile conditions is readily accomplishedby standard pharmaceutical techniques well-known to those skilled in theart.

The compositions of the present invention may be administered by directinjection.

The compounds of the invention may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

Alternatively the composition may be formulated for topical application,for example in the form of ointments, creams, lotions, eye ointments,eye drops, ear drops, mouthwash, impregnated dressings and sutures andaerosols, and may contain appropriate conventional additives, including,for example, preservatives, solvents to assist drug penetration, andemollients in ointments and creams. Such topical formulations may alsocontain compatible conventional carriers, for example cream or ointmentbases, and ethanol or oleyl alcohol for lotions. Such carriers mayconstitute from about 1% to about 98% by weight of the formulation; moreusually they will constitute up to about 80% by weight of theformulation.

For application topically to the skin, the agent of the presentinvention can be formulated as a suitable ointment containing the activecompound suspended or dissolved in, for example, a mixture with one ormore of the following: mineral oil, liquid petrolatum, white petrolatum,propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifyingwax and water.

Alternatively, it can be formulated as a suitable lotion or cream,suspended or dissolved in, for example, a mixture of one or more of thefollowing: mineral oil, sorbitan monostearate, a polyethylene glycol,liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkanesuch as tetrafluoroethane or heptafluoropropane, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges of e.g. gelatin for use in an inhaler or insufflator maybe formulated containing a powder mix of a compound of the invention anda suitable powder base such as lactose or starch.

Alternatively, the compound of the present invention can be administeredin the form of a suppository or pessary, or it may be applied topicallyin the form of a gel, hydrogel, lotion, solution, cream, ointment ordusting powder.

The compounds of the present invention may also be administered by thepulmonary or rectal routes. They may also be administered by the ocularroute. For ophthalmic use, the compounds can be formulated as micronisedsuspensions in isotonic, pH adjusted, sterile saline, or, preferably, assolutions in isotonic, pH adjusted, sterile saline, optionally incombination with a preservative such as a benzylalkonium chloride.Alternatively, they may be formulated in an ointment such as petrolatum.

The pharmaceutical compositions generally are administered in an amounteffective for treatment or prophylaxis of a specific condition orconditions. Initial dosing in humans is accompanied by clinicalmonitoring of symptoms, such symptoms for the selected condition. Ingeneral, the compositions are administered in an amount of active agentof at least about 100 μg/kg body weight. In most cases they will beadministered in one or more doses in an amount not in excess of about 20mg/kg body weight per day. Preferably, in most cases, dose is from about100 μg/kg to about 5 mg/kg body weight, daily. For administrationparticularly to mammals, and particularly humans, it is expected thatthe daily dosage level of the active agent will be from 0.1 mg/kg to 10mg/kg and typically around 1 mg/kg. It will be appreciated that optimumdosage will be determined by standard methods for each treatmentmodality and indication, taking into account the indication, itsseverity, route of administration, complicating conditions and the like.The physician in any event will determine the actual dosage which willbe most suitable for an individual and will vary with the activity ofthe specific compound to be employed, the metabolic stability and lengthof action of that compound, age, weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination,severity of the particular condition and response of the particularindividual. The effectiveness of a selected actual dose can readily bedetermined, for example, by measuring clinical symptoms or standardanti-inflammatory indicia after administration of the selected dose. Theabove dosages are exemplary of the average case. There can, of course,be individual instances where higher or lower dosage ranges are merited,and such are within the scope of this invention. For conditions ordisease states as are treated by the present invention, maintainingconsistent daily levels in a subject over an extended period of time,e.g., in a maintenance regime, can be particularly beneficial. For oraland parenteral administration to humans, the daily dosage level of theagent may be in single or divided doses.

In another aspect, the present invention provides a compound of formula(I) or a pharmaceutically acceptable derivative thereof, for use intherapy.

The compounds of the present invention are generally inhibitors of theserine/threonine kinase p38 and are therefore also inhibitors ofcytokine production which is mediated by p38 kinase. Within the meaningof the term “inhibitors of the serine/threonine kinase p38” are includedthose compounds that interfere with the ability of p38 to transfer aphosphate group from ATP to a protein substrate according to the assaydescribed below.

It will be appreciated that the compounds of the invention may beselective for one or more of the isoforms of p38, for example p38α,p38β, p38γ and/or p386δ. In one embodiment, the compounds of theinvention selectively inhibit the p38α isoform. In another embodiment,the compounds of the invention selectively inhibit the p38β isoform. Ina further embodiment, the compounds of the invention selectively inhibitthe p38α and p38β isoforms. Assays for determining the selectivity ofcompounds for the p38 isoforms are described in, for example, WO99/61426, WO 00/71535 and WO 02/46158.

It is known that p38 kinase activity can be elevated (locally orthroughout the body), p38 kinase can be incorrectly temporally active orexpressed, p38 kinase can be expressed or active in an inappropriatelocation, p 38 kinase can be constitutively expressed, or p 38 kinaseexpression can be erratic; similarly, cytokine production mediated byp38 kinase activity can be occurring at inappropriate times,inappropriate locations, or it can occur at detrimentally high levels.

Accordingly, the present invention provides a compound of formula (I) ora pharmaceutically acceptable derivative thereof for use in thetreatment or prophylaxis of a condition or disease state mediated by p38kinase activity or mediated by cytokines produced by the activity of p38kinase.

The present invention also provides a method for the treatment of acondition or disease state mediated by p38 kinase activity, or mediatedby cytokines produced by the activity of p38 kinase, in a subject whichcomprises administering to said subject a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablederivative thereof. The compound may be administered as a single orpolymorphic crystalline form or forms, an amorphous form, a singleenantiomer, a racemic mixture, a single stereoisomer, a mixture ofstereoisomers, a single diastereoisomer or a mixture ofdiastereoisomers.

The present invention also provides a method of inhibiting cytokineproduction which is mediated by p38 kinase activity in a subject, e.g. ahuman, which comprises administering to said subject in need of cytokineproduction inhibition a therapeutic, or cytokine-inhibiting, amount of acompound of the present invention. The compound may be administered as asingle or polymorphic crystalline form or forms, an amorphous form, asingle enantiomer, a racemic mixture, a single stereoisomer, a mixtureof stereoisomers, a single diastereoisomer or a mixture ofdiastereoisomers.

The present invention treats these conditions by providing atherapeutically effective amount of a compound of this invention. By“therapeutically effective amount” is meant a symptom-alleviating orsymptom-reducing amount, a cytokine-reducing amount, acytokine-inhibiting amount, a kinase-regulating amount and/or akinase-inhibiting amount of a compound. Such amounts can be readilydetermined by standard methods, such as by measuring cytokine levels orobserving alleviation of clinical symptoms. For example, the cliniciancan monitor accepted measurement scores for anti-inflammatorytreatments. It will be appreciated that reference to treatment includesacute treatment or prophylaxis as well as the alleviation of establishedsymptoms.

The compounds of the present invention can be administered to anysubject in need of inhibition or regulation of p38 kinase or in need ofinhibition or regulation of p38 mediated cytokine production. Inparticular, the compounds may be administered to mammals. Such mammalscan include, for example, horses, cows, sheep, pigs, mice, dogs, cats,primates such as chimpanzees, gorillas, rhesus monkeys, and, mostpreferably, humans.

Thus, the present invention provides methods of treating or reducingsymptoms in a human or animal subject suffering from, for example,rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema,allergic rhinitis, allergic conjunctivitis, adult respiratory distresssyndrome, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, silicosis, endotoxemia, toxic shocksyndrome, inflammatory bowel disease, tuberculosis, atherosclerosis,neurodegenerative disease, Alzheimer's disease, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiplesclerosis, aneurism, stroke, irritable bowel syndrome, muscledegeneration, bone resorption diseases, osteoporosis, diabetes,reperfusion injury, graft vs. host reaction, allograft rejections,sepsis, systemic cachexia, cachexia secondary to infection ormalignancy, cachexia secondary to acquired immune deficiency syndrome(AIDS), malaria, leprosy, infectious arthritis, leishmaniasis, Lymedisease, glomerulonephritis, gout, psoriatic arthritis, Reiter'ssyndrome, traumatic arthritis, rubella arthritis, Crohn's disease,ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, andnon articular inflammatory conditions, for example,herniated/ruptured/prolapsed intervertebral disk syndrome, bursitis,tendonitis, tenosynovitis, fibromyalgic syndrome and other inflammatoryconditions associated with ligamentous sprain and regionalmusculoskeletal strain, pain, for example that associated withinflammation and/or trauma, osteopetrosis, restenosis, thrombosis,angiogenesis, cancer including breast cancer, colon cancer, lung canceror prostatic cancer, which comprises administering to said subject atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable derivative thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, systemic cachexia, glomerulonephritis,Crohn's disease, neurodegenerative disease, Alzheimer's disease,Parkinson's disease, epilepsy and cancer including breast cancer, coloncancer, lung cancer and prostatic cancer, which comprises administeringto said subject a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable derivative thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonarydisease, chronic heart failure, systemic cachexia, glomerulonephritis,Crohn's disease and cancer including breast cancer, colon cancer, lungcancer and prostatic cancer, which comprises administering to saidsubject a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable derivative thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from rheumatoid arthritis, asthma,chronic pulmonary inflammation, chronic obstructive pulmonary disease,neurodegenerative disease, Alzheimer's disease, Parkinson's disease andepilepsy which comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from any type of pain includingchronic pain, rapid onset of analgesis, neuromuscular pain, headache,cancer pain, acute and chronic inflammatory pain associated withosteoarthritis and rheumatoid arthritis, post operative inflammatorypain, neuropathic pain, diabetic neuropathy, trigeminal neuralgia,post-hepatic neuralgia, inflammatory neuropathies and migraine painwhich comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof.

A further aspect of the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable derivative thereof, in themanufacture of a medicament for use in the treatment of a condition ordisease state mediated by p38 kinase activity or mediated by cytokinesproduced by p38 kinase activity.

The compounds of formula (I) and their derivatives may be employed aloneor in combination with other therapeutic agents for the treatment of theabove-mentioned conditions. The invention thus provides, in a furtheraspect, a combination comprising a compound of the invention or apharmaceutically acceptable derivative thereof together with a furthertherapeutic agent.

In particular, in rheumatoid arthritis therapy, combination with otherchemotherapeutic or antibody agents is envisaged. Combination therapiesaccording to the present invention thus comprise the administration ofat least one compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof and at least one other pharmaceutically activeagent. The compound(s) of formula (I) or pharmaceutically acceptablesalt(s) or solvate(s) thereof and the other pharmaceutically activeagent(s) may be administered together or separately and, whenadministered separately, this may occur separately or sequentially inany order. The amounts of the compound(s) of formula (I) orpharmaceutically acceptable salt(s) or solvate(s) thereof and the otherpharmaceutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect. Appropriate doses will be readily appreciated bythose skilled in the art. It will be appreciated that the amount of acompound of the invention required for treatment will vary with thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or veterinarian. Examples of other pharmaceutically activeagents which may be employed in combination with compounds of formula(I) and their salts and solvates for rheumatoid arthritis therapyinclude: immunosuppressants such as amtolmetin guacil, mizoribine andrimexolone; anti-TNFα agents such as etanercept, infliximab, diacerin;tyrosine kinase inhibitors such as leflunomide; kallikrein antagonistssuch as subreum; interleukin 11 agonists such as oprelvekin; interferonbeta 1 agonists; hyaluronic acid agonists such as NRD-101 (Aventis);interleukin 1 receptor antagonists such as anakinra; CD8 antagonistssuch as amiprilose hydrochloride; beta amyloid precursor proteinantagonists such as reumacon; matrix metalloprotease inhibitors such ascipemastat and other disease modifying anti-rheumatic drugs (DMARDs)such as methotrexate, sulphasalazine, cyclosporin A, hydroxychloroquine,auranofin, aurothioglucose, gold sodium thiomalate and penicillamine.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention.

The individual components of such combinations may be administeredeither sequentially or simultaneously in separate or combinedpharmaceutical formulations by any convenient route.

When administration is sequential, either the compound of the inventionor the second therapeutic agent may be administered first. Whenadministration is simultaneous, the combination may be administeredeither in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation. When formulated separately they maybe provided in any convenient formulation, conveniently in such manneras are known for such compounds in the art.

EXAMPLES

The following Examples are illustrative embodiments of the invention,not limiting the scope of the invention in any way. Reagents arecommercially available or are prepared according to procedures in theliterature.

{5-[(Cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid,N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide,4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid maybe prepared by the procedures described in WO 03/068747.

(4-Fluoro-2-methylphenyl)boronic acid may be prepared by the proceduredescribed by J. B. Doherty, et al. in WO 02/058695.

5-Bromoindazole may be prepared by the procedure described by A. Arnautuet al. in Tetrahedron Letters, 2002, 43, 2695.

3-(Bromomethyl)-5-methylisoxazole and 4-hydrazino-2,6-dimethylpyrimidinemay be purchased from Maybridge International.

[4-(4-Morpholinyl)phenyl]boronic acid may be purchased from AsymChemInternational.

5-Bromo-1-(2-pyridinyl)-1H-indole, 5-bromo-1-(3-pyridinyl)-1H-indole and3-(5-bromo-1H-indol-1-yl)benzonitrile may be prepared by the proceduresdescribed by G. H. Ladouceur, et al. in WO 03/027094.

4-Methylsulfonylphenylhydrazine may be purchased from Apin Chemical Ltd.

2-(4-Aminophenyl)-N-methylacetamide may be prepared by the proceduredescribed by J. A. Cipollina, et al. in EP 666 258 A1.

Tetrahydro-2H-pyran-4-ylamine may be prepared by the procedure describedby M Allegretti, et al. in Tetrahedron Letters, 2001, 42, 57.

6-Hydrazino-4(1H)-pyrimidinone may be prepared by the proceduredescribed by B. E. Christensen, et al. in Journal of Organic Chemistry,1971, 36, 2462.

6-Bromo-3-[4-(methyloxy)phenyl]-1,2-benzisoxazole and4-(6-bromo-1,2-benzisoxazol-3-yl)phenol may be prepared by theprocedures described by J. Aebi, et al. in EP 778 271 A2.

2-Aminopyridazine may be purchased from Sigma-RBI.

(4-Bromo-2-fluorophenyl)(4-fluorophenyl)methanone and(4-bromo-2-fluorophenyl)[4-(methyloxy)phenyl]methanone may be preparedby the procedures described by A Levy et al. in Journal of OrganicChemistry, 2003, 68, 3990.

LCMS was conducted on a column (3.3 cm×4.6 mm ID, 3 μm ABZ+PLUS), at aFlow Rate of 3 ml/min, Injection Volume of 5 μl, at room temperature andUV Detection Range at 215 to 330 nm. Solvent A: 10 mM Aqueous ammoniumacetate+0.1% formic acid. Solvent B: 95% Acetonitrile+0.05% formic acid.Gradient: 0% A/0.7 min, 0-100% A/3.5 min, 100% A/1.1 min, 100-0% A/0.2min.

Intermediate 1 5-Bromo-1-phenyl-1H-indazole

A solution of 5-bromo-2-fluorobenzaldehyde (10.0 g) in boilingacetonitrile (90 ml) was added to a solution of phenylhydrazine (8.3 g)in boiling acetonitrile (360 ml). The yellow solution was stirred for 5min, allowed to cool then concentrated under vacuum. The resulting solidwas washed with hexane (3×10 ml) and the residue was dissolved in DMSO(125 ml). Cesium carbonate (32.9 g) was added and the mixture was heatedat 140° C. for 24 h then at 150° C. for 40 h. The reaction mixture wasdiluted with ethyl acetate (600 ml) then washed with saturated sodiumhydrogen carbonate (2×300 ml) and brine (2×300 ml). The solvent wasremoved under vacuum and the residue was recrystallised from methanol togive the title compound as a white solid (6.98 g).

LC-MS: Rt 3.19 min, MH+ 273/275.

Intermediate 2 5-Bromo-1-(4-fluorophenyl)-1H-indazole

A solution of 4-fluorophenylhydrazine hydrochloride (27.4 g) in ethylacetate (50 ml), was washed with saturated sodium hydrogen carbonate(3×20 ml), dried and concentrated under vacuum. The resulting oil wasdissolved in boiling acetonitrile (36 ml) and a solution of5-bromo-2-fluorobenzaldehyde (20 g) in boiling a cetonitrile (9 ml) wasadded. The solution was allowed to cool, the solvent was evaporated andthe residue was dissolved in DMSO (200 ml). Cesium carbonate added andthe mixture was heated by microwave in a sealed vessel at 200° C. for 10min. The reaction mixture was diluted with ethyl acetate (1000 ml) thenwashed with hydrochloric acid (1M, 3×200 ml), saturated sodium hydrogencarbonate (2×200 ml) and brine (200 ml). The organic phase was dried andconcentrated under vacuum and the residue was recrystallised from hexaneto give the title compound as a white crystalline solid (16.98 g).

LC-MS: Rt 3.13 min, MH+ 291/293.

Intermediate 3 tert-Butyl 5-bromo-1H-indazole-1-carboxylate

A stirred ice-cold suspension of 5-bromoindazole (2 g),4-(dimethylamino)pyridine (250 mg) and triethylamine (1.55 ml) inacetonitrile (50 ml) was treated with a solution of di-tert-butyldicarbonate (2.8 ml) in acetonitrile (20 ml) over 15 min such that thetemperature remained under 5° C. The reaction mixture was warmed to roomtemperature then stirred for 18 h. The solvent was evaporated and theresidue was purified by column chromatography on silica (100 g) elutingwith cyclohexane:ethyl acetate (15:1) to give the title compound (2.27g).

LCMS: Rt 3.55 min.

Intermediate 4 1,1-Dimethylethyl5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazole-1-carboxylate

A mixture of tert-butyl 5-bromo-1H-indazole-1-carboxylate (Intermediate3, 1.07 g),{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid(0.85 g), sodium carbonate (1.9 g) andtetrakis(triphenylphosphine)palladium(0) (0.42 g) in 1,2-dimethoxyethane(70 ml) was stirred at reflux under nitrogen for 20 h. The solvent wasremoved and the residue was partitioned between water (50 ml) and ethylacetate (50 ml). The aqueous layer was re-extracted with ethyl acetate(3×30 ml) and the combined organic extracts were dried using ahydrophobic filter tube and concentrated under vacuum. The residue waspurified by column chromatography on silica eluting withcyclohexane:ethyl acetate (75:25 to 60:40) to give the title compound(3.1 g).

LCMS: Rt 3.46 min, MH+410.

Intermediate 5N-Cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide

A mixture of 1,1-dimethylethyl5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazole-1-carboxylate(Intermediate 4, 0.46 g) in a solution of hydrogen chloride in dioxan(4M, 7 ml) was stirred at room temperature under nitrogen for 4.5 h. Thesolvent was evaporated and the residue was partitioned betweendichloromethane (20 ml) and aqueous sodium hydroxide (2M, 20 ml). Theorganic layer was separated using a hydrophobic filter tube, the solventwas evaporated and the residue was purified on a Varian Bond-Elut SPEcartridge (silica, 10 g) eluting with chloroform:methanol (100:0 to98:2) to give the title compound (0.06 g).

LCMS: Rt 2.96 min, MH+310.

Intermediate 6(N-Cyclobutyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

A mixture of4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(262 mg) in chloroform (10 ml) was stirred with3-{[(ethylimino)methylidene]amino}-N,N,N-trimethyl-1-propanaminiumiodide (450 mg), 1-hydroxy-7-azabenzotriazole (13 mg) andcyclobutylamine (102 μl) for 18 h. Water was added, the organic layerwas separated using a hydrophobic filter tube and the solvent wasremoved under vacuum to give the title compound (210 mg).

NMR: [δH d₆-DMSO] 8.59 (1H d, J=8 Hz), 8.08 (1H, d, J=1 Hz), 7.81 (1H,dd, 8 Hz J=1 Hz), 7.26 (1H, d, J=8 Hz), 4.47-4.37 (1H, m), 2.50 (3H, s),2.25-2.15 (2H, m), 2.14-2.03 (2H, m), 1.70-1.62 (2H, m), 1.32 (12H, s).

Intermediate 7 Methyl 3-fluoro-5-iodo-4-methylbenzoate

A stirred mixture of 3-fluoro-4-methylbenzoic acid (10.3 g) intrifluoromethane sulfonic acid (50 ml) at −20° C. was treated withN-iodosuccinimide in portions over 40 min. The reaction was stirred at−10° C. for 44 h when a further amount of N-iodosuccinimide (6.0 g) wasadded. After 20 h the reaction mixture was added to ice/water andextracted with ethyl acetate. The organic solution was washed withaqueous sodium metabisulfite and dried over sodium sulfate. The residuewas dissolved in methanol (50 ml), the solution was treated withconcentrated sulfuric acid (91 ml) and the mixture was heated at refluxfor 6 h. The solvent was evaporated and the residue was dissolved inethyl acetate. This solution was washed with aqueous sodium bicarbonateand dried with brine and over magnesium sulfate. Purification by biotagechromatography (x2), firstly using cyclohexane/ethyl acetate (100/1) andsecondly cyclohexane/toluene (6/1) as eluents gave the title compound(9.31 g).

LC-MS: Rt 3.55 min.

Intermediate 8 Methyl3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of methyl 3-fluoro-5-iodo-4-methylbenzoate (Intermediate 7,9.04 g), potassium acetate (15.06 g), bis(pinacolato)diborane (11.7 g)and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (251mg) in DMF (200 ml) was deoxygenated then stirred at 90° C. for 18 h.The reaction mixture was evaporated to dryness, pre-absorbed on tosilica and purified by Biotage chromatography using a cyclohexane/ethylacetate gradient as eluent to give the title compound (8.39 g).

LC-MS: Rt 3.78 min.

Intermediate 9 3-Fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzoicacid

A mixture of 5-bromo-1-phenyl-1H-indazole (Intermediate 1, 272 mg),methyl3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(Intermediate 8, 294 mg), tetrakis(triphenylphoshine)palladium (0) (30mg) and 1M aqueous sodium bicarbonate (10 ml) in isopropanol (10 ml) washeated at reflux for 3 h. The reaction mixture was acidified with 2Mhydrochloric acid then diluted with ethyl acetate. The organic layer wasseparated using a hydrophobic filter tube, the solvent was evaporatedand the residue was purified on an SPE cartridge (silica) eluting with apetroleum ether/ethyl acetate gradient containing 0.1% acetic acid togive the title compound as a colourless solid (227 mg).

LC-MS: Rt 3.94 min MH+347.

Intermediate 10 4-(5-Bromo-1H-indol-1-yl)benzonitrile

A solution of 5-bromo-1H-indole (196 mg) and sodium hydride (60%dispersion in mineral oil, 24 mg) in DMF (6 ml) was stirred at roomtemperature under nitrogen for 1 h. A solution of 4-fluorobenzonitrile(446 mg) in DMF (0.5) was added and the resulting mixture was stirred at100° C. under nitrogen for 12 h. The mixture was partitioned betweenwater and ethyl acetate and the organic layer was washed with water andbrine, dried through a hydrophobic filter tube and concentrated undervacuum. The residue was partially purified on an SPE cartridge (silica,5 g) eluting with cyclohexane:ethyl acetate (99:1 to 1:1) to give impuretitle compound as a yellow oil.

LC-MS: Rt 3.27.

Intermediate 11 5-Bromo-1-(3-methylphenyl)-1H-indazole

A mixture of 3-methylphenylhydrazine (240 mg) and5-bromo-2-fluorobenzaldehyde (0.2 ml) in acetonitrile (1 ml) was stirredat room temperature for 1 h. The solvent was removed under vacuum andthe residue was dissolved in DMSO (2 ml). Cesium carbonate (510 mg) wasadded and the mixture was heated in a microwave oven at 200° C. for 10min. The reaction mixture was diluted with ethyl acetate (10 ml) thenwashed with hydrochloric acid (1M), aqueous sodium hydrogen carbonateand brine. The solvent was removed under vacuum and the residue waspurified using an SPE cartridge (silica), eluting with cyclohexane togive the title compound as a yellow oil (157 mg).

LC-MS: Rt 3.81 min, MH+287, 289.

Intermediate 12 5-Bromo-1-[4-(trifluoromethyl)phenyl]-1H-indazole

The procedure for Intermediate 11 was followed using4-trifluoromethylphenylhydrazine (300 mg), 5-bromo-2-fluorobenzaldehyde(0.2 ml), a cetonitrile (1 ml), DMSO (2 ml) and cesium carbonate (580mg) to give the title compound (202 mg).

LC-MS: Rt 3.90 min.

Intermediate 13 5-Bromo-1-[4-(methylsulfonyl)phenyl]-1H-indazole

The procedure for Intermediate 11 was followed using4-methylsulfonylphenylhydrazine (333 mg), 5-bromo-2-fluorobenzaldehyde(0.21 ml), acetonitrile (1 ml), DMSO (2 ml) and cesium carbonate (650mg) to give the title compound as a yellow solid (470 mg).

LC-MS: Rt 3.24 min, MH+351, 353.

Intermediate 14 2-(4-Hydrazinophenyl)-N-methylacetamide, hydrochloride

Sodium nitrite (8.5 g) in water (18 ml) was added over 30 min to astirred solution of 2-(4-aminophenyl)-N-methylacetamide (20 g) inconcentrated hydrochloric acid (41 ml) at −7° C. The reaction mixturewas stirred for 1 h at −5° C. then added over 30 min to a solution oftin (II) chloride dihydrate (136.5 g) in concentrated hydrochloric acid(160 ml) maintaining a temperature below 0° C. throughout. The reactionwas stirred at −5° C. for 2 h and the white precipitate was collected byfiltration and washed with ether (2×30 ml). The solid was dissolved inhot methanol (110 ml), filtered through Hyflo™ then treated with hotisopropyl acetate (325 ml). The solution was allowed to cool, chilled inan ice bath and the resulting precipitate was collected by filtration,washed with isopropyl acetate (2×25 ml) and dried to give the titlecompound as a white solid (22.2 g).

Microanalysis: Found. C, 49.09; H, 6.53; N, 18.92.

-   -   Calculated for C₉H₁₃N₃O·HCl·0.25H₂O: C, 49.09; H, 6.64; N,        19.08.

Intermediate 15 2-[4-(5-Bromo-1H-indazol-1-yl)phenyl]-N-methylacetamide

The procedure for Intermediate 11 was followed using2-(4-hydrazinophenyl)-N-methylacetamide (Intermediate 14, 333 mg),5-bromo-2-fluorobenzaldehyde (0.21 ml), acetonitrile (1 ml), DMSO (2 ml)and cesium carbonate (650 mg) to give the title compound as a brownsolid (495 mg).

LC-MS: Rt 3.09 min, MH+344, 346.

Intermediate 16N-Cyclopropyl-4′,5-difluoro-3′-formyl-6-methyl-3-biphenylcarboxamide

5-Bromo-2-fluorobenzaldehyde (0.48 ml),{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid(1.1 g), tetrakis(triphenylphosphine) palladium (101 mg) and aqueoussodium hydrogen carbonate (1M, 8 ml) were combined in isopropanol (16ml) and heated at 85° C. for 18 h. The cooled mixture was absorbed ontosilica and applied to an SPE cartridge (silica, 50 g). Elution withcyclohexane/ethyl acetate (4:1 to 1:1) gave the title compound as ayellow oil (650 mg).

LC-MS: Rt 3.09 min, MH+316.

Intermediate 17N-(4-Fluorophenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

The procedure for Intermediate 6 was followed using4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(655 mg),3-{[(ethylimino)methylidene]amino}-N,N,N-trimethyl-1-propanaminiumiodide (719 mg), 1-hydroxy-7-azabenzotriazole (34 mg) and4-fluoroaniline (360 μl) in chloroform (10 ml). The crude product, inmethanol (30 ml) was applied to an SCX cartridge and eluted withmethanol to give the title compound as a pink foam (780 mg).

LC-MS: Rt 3.62 min.

Intermediate 18N-Ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

The procedure for Intermediate 6 was followed using4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(1.31 g),3-{[(ethylimino)methylidene]amino}-N,N,N-trimethyl-1-propanaminiumiodide (2.23 g), 1-hydroxy-7-azabenzotriazole (68 mg) and a solution ofethylamine in THF (2M, 5 ml) in chloroform (30 ml). The crude product,in methanol was applied to an SCX cartridge and eluted with methanol togive the title compound as a pale yellow solid (1.36 g).

LC-MS: Rt 3.20 min.

Intermediate 19 1,1-Dimethylethyl(2Z)-2-[(4-bromo-2-fluorophenyl)(4-fluorophenyl)methylidene]hydrazinecarboxylate

A mixture of (4-bromo-2-fluorophenyl)(4-fluorophenyl)methanone (176 mg),tert-butyl carbazate (76 mg) and acetic acid in methanol (4 ml) wasstirred at reflux for 66 h. The reaction mixture was partitioned betweenwater and ethyl acetate, the phases were separated and the organic layerwas washed with water and brine. The dried (Na₂SO₄) extracts wereconcentrated under vacuum and the residue was purified on a SPEcartridge (silica, 5 g) eluting with cyclohexane/ethyl acetate (9:1) togive the title compound as a white solid (141 mg).

LC-MS: Rt 3.71 min.

Intermediate 20 6-Bromo-3-(4-fluorophenyl)-1H-indazole

A solution of 1,1-dimethylethyl(2Z)-2-[(4-bromo-2-fluorophenyl)(4-fluorophenyl)methylidene]hydrazinecarboxylate(Intermediate 19, 141 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (32 μl)in THF (5 ml) was heated at 150° C. for 30 min in a microwave oven.Water and chloroform were added and the organic layer was separatedusing a hydrophobic filter tube. The solvent was evaporated and theresidue was purified on an SPE cartridge (silica, 2 g) eluting withcyclohexane/ethyl acetate (100:0 to 80:20) to give the title compound(42 mg).

LC-MS: Rt 3.71 min.

Intermediate 21 1,1-Dimethylethyl2-{(4-bromo-2-fluorophenyl)[4-(methyloxy)phenyl]methylidene}

The procedure for Intermediate 19 was followed using(4-bromo-2-fluorophenyl)[4-(methyloxy)phenyl]methanone (183 mg)tert-butyl carbazate (76 mg) acetic acid (0.4 ml) and methanol (4 ml) togive the title compound as a yellow solid (110 mg).

LC-MS: Rt 3.62 min.

Intermediate 22 6-Bromo-3-[4-(methyloxy)phenyl]-1H-indazole

The procedure for Intermediate 20 was followed using 1,1-dimethylethyl2-{(4-bromo-2-fluorophenyl)[4-(methyloxy)phenyl]methylidene}hydrazinecarboxylateIntermediate 21, 110 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (39 μl)and THF (5 ml) to give the title compound (53 mg).

LC-MS: Rt 3.62 min.

Intermediate 23 N-Ethyl-3-(1H-indazol-6-yl)-4-methylbenzamide

A stirred mixture of 6-iodo-1H-indazole (0.45 g),N-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 18, 0.54 g) tetrakis(triphenylphosphine)palladium(0) (0.05g) and aqueous sodium hydrogen carbonate (1M, 1 ml) in isopropanol (10ml) was heated at 150° C. for 30 min in a microwave oven. The reactionmixture was poured into water (50 ml) and extracted with ethyl acetate(3×25 ml). The extracts were washed with water (25 ml) dried (Na₂SO₄)and concentrated under vacuum. The residual oil was purified by columnchromatography on silica (50 g) eluting with ether/ethyl acetate (7:3)to give the title compound as a pale yellow foam (0.25 g). LC-MS: Rt 2.7min.

Intermediate 24 N-Ethyl-3-(3-iodo-1H-indazol-6-yl)-4-methylbenzamide

Iodine (1.35 g) was added to a stirred solution ofN-ethyl-3-(1H-indazol-6-yl)-4-methylbenzamide (Intermediate 23, 1.1 g)in 1,4-dioxan (20 ml) and aqueous sodium hydroxide (2M, 20 ml) thenstirred at room temperature for 10 min. The reaction mixture was treatedwith aqueous sodium bisulphite (10%, 25 ml) and aqueous citric acid(10%, 25 ml). The mixture was extracted with ethyl acetate (3×25 ml) andthe organic extracts were washed with water (30 ml) dried (Na₂SO₄) andconcentrated under vacuum to give the title-compound (1.54 g).

LC-MS: Rt 3.29 min, MH⁺406.

Intermediate 25 N-Ethyl-3-fluoro-5-iodo-4-methylbenzamide

3-Fluoro-5-iodo-4-methylbenzoic acid (Intermediate 69, 20 g) in thionylchloride (20 ml) was heated at 110° C. for 1 h. The excess thionylchloride was evaporated under vacuum and the residual oil was dissolvedin DCM (100 ml). Potassium carbonate (21 g) was added to the solutionfollowed by the slow addition of ethylamine (2M in THF, 70 ml). Thereaction was left at room temperature overnight, filtered and theresidue was washed with ethyl acetate. The combined filtrate andwashings were reduced to dryness under vacuum and the resulting solidwas washed with ether/cyclohexane (1:1) to give the title compound as apale beige solid (18.5 g).

NMR: [δH d₆-DMSO] 8.58 (1H, b), 8.15 (1H, s), 7.64 (1H, d), 3.26 (2H,quin), 2.33 (3H, s), 1.11 (3H, t).

Intermediate 26{5-[(Ethylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid

Sodium hydride (60% in mineral oil, 1.23 g) was added in portions to asolution of N-ethyl-3-fluoro-5-iodo-4-methylbenzamide (Intermediate 25,4.81 g) in anhydrous THF (75 ml). The resulting mixture was cooled to−75° C. and n-butyllithium (1.6M in hexanes, 20 ml) was added dropwiseover 20 min. Triisopropylborate (8 ml) was added over 5 min and thereaction mixture was stirred at −75° C. for 6 h. Water (20 ml) was addedand the mixture was warmed to 15° C. overnight and the mixture waspartitioned between saturated aqueous ammonium chloride and ethylacetate. The organic phase was washed with aqueous ammonium chloride andbrine, dried (MgSO₄) and concentrated under vacuum. The residue wasdissolved in DCM and applied to a silica column (10 g) eluting with anethyl acetate/dichloromethane gradient (0-100% ethyl acetate) followedby methanol. The methanol fractions were concentrated under vacuum togive the title compound as an off-white foam (550 mg).

NMR: [δH d₄-MeOH] 7.55 (1H, s), 7.48 (1H, d), 3.38 (2H, q), 3.30 (2H,b), 2.28, (3H, s), 1.20 (3H, t).

Intermediate 27N-Ethyl-3-fluoro-5-(3-iodo-1H-indazol-6-yl)-4-methylbenzamide

A stirred mixture of 6-iodo-1H-indazole (0.5 g){5-[(ethylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid(Intermediate 16, 0.56 g), tetrakis(triphenylphosphine)palladium(0)(0.05 g) and aqueous sodium hydrogen carbonate (1M, 1 ml) in isopropanol(10 ml) was heated at 150° C. for 30 min in a microwave oven. Thereaction mixture was poured into water (30 ml) and extracted with ethylacetate (3×20 ml). The extracts were dried (Na₂SO₄) and concentratedunder vacuum. The residual oil was purified by column chromatography onsilica (50 g) eluting with ether/ethyl acetate (4:1). The resultantproduct was triturated with a small quantity of dichloromethane to givethe title compound as a pale yellow solid (0.15 g).

LC-MS: Rt 2.96 min, MH+298.

Intermediate 28N-Ethyl-3-fluoro-5-(3-iodo-1H-indazol-6-yl)-4-methylbenzamide

Iodine (0.153 g) was added to a stirred solution ofN-ethyl-3-fluoro-5-(3-iodo-1H-indazol-6-yl)-4-methylbenzamide(Intermediate 27, 0.15 g) in 1,4-dioxan (4 ml) and aqueous sodiumhydroxide (2M, 4 ml) then stirred at room temperature for 45 min. Thereaction mixture was treated aqueous citric acid (20%, 20 ml) followedby sodium metabisulphite (2 g). The mixture was diluted with water thenextracted with ethyl acetate (2×30 ml). The organic extracts were washedwith water (30 ml) dried (Na₂SO₄) and concentrated under vacuum to givethe title compound as a pale yellow foam (0.21 g).

LC-MS: Rt 3.41 min, MH⁺424.

Intermediate 29(4-Bromo-2-fluorophenyl)[6-(methyloxy)-3-pyridinyl]methanone

A mixture of 6-(methyloxy)-3-pyridinecarboxylic acid (0.306 g) andthionyl chloride (6 ml) was stirred at reflux for 2 h and the solventwas removed under vacuum. The residue was co-evaporated with THF (x2) toremove residual thionyl chloride. A mixture of the residue andtetrakis(triphenylphosphine)palladium(0) (20 mg) in dry THF (5 ml) wastreated with a solution of (4-bromo-2-fluorophenyl)(iodo)zinc in THF(0.5M, 8.1 ml) then stirred at room temperature for 1.5 h. The reactionmixture was treated with 1 aqueous ammonium chloride (1M) then dilutedwith ethyl acetate and aqueous ammonium chloride. The organic layer wasseparated using a hydrophobic filter tube and concentrated under vacuum.The residue was purified on a SPE cartridge (silica, 50 g) eluting withcyclohexane/ethyl acetate (100:0 to 0:100) to give impure title compound(0.331 g) as an amber oil.

LC-MS: Rt 3.3 min MH+310/312.

Intermediate 30 6-Bromo-3-[6-(methyloxy)-3-pyridinyl]-1H-indazole

A mixture of impure(4′-bromo-2′,3-difluoro-4-biphenylyl)[6-(methyloxy)-3-pyridinyl]methanone(0.33 g) in methanol (5 ml) was treated with 1,1-dimethylethylhydrazinecarboxylate (93 mg) and acetic acid (0.1 ml) then stirred atreflux for 24 h. More 1,1-dimethylethyl hydrazinecarboxylate (57 mg) andacetic acid (20 μl) were added and heating was continued for a further24 h. The reaction mixture was diluted with dichloromethane and stirredrapidly with saturated aqueous sodium bicarbonate. The organic layer wasseparated using a hydrophobic filter tube and concentrated under vacuum.The residue was purified by column chromatography on silica, elutingwith cyclohexane:ethyl acetate (100:0 to 0:100). The isolated product,in THF (4.5 ml) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (150μl) and heated in a sealed tube in a microwave oven at 150° C. for 30min. The solvent was evaporated and the residue was purified by columnchromatography on silica eluting with cyclohexane:ethyl acetate (100:0to 0:100) to give the title compound (59 mg).

LC-MS: Rt 3.5 min, MH⁺304/306.

Intermediate 31N-Ethyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

N-Ethyl-3-fluoro-5-iodo-4-methylbenzamide (Intermediate 25, 10.9 g),bispinnacolcatodiborane (9.9 g), Pd(dppf)Cl₂ (600 mg) and potassiumacetate (17.3 g) were mixed in DMF (210 ml). The mixture was degassedand then heated at 85° C. under nitrogen for 18 h. The cooled reactionwas absorbed onto silica and applied to a silica column, eluting with anethyl acetate/cyclohexane gradient (5-25% ethyl acetate). The resultantproduct was recrystallised from cyclohexane to give the title compoundas a white solid (2.83 g).

NMR: [δH d₆-DMSO] 8.54 (1H, bt), 7.94 (1H, s), 7.68 (1H, d), 3.27, (2H,quin), 2.42 (3H, s), 1.32 (12H, s), 1.11 (3H, t).

Intermediate 32 (4-Bromo-2-fluorophenyl)(2-pyridinyl)methanone

A mixture of picolinoyl chloride hydrochloride (356 mg) andtetrakis(triphenylphosphine)palladium(0) (50 mg) in THF (10 ml) wasadded to (4-bromo-2-fluorophenyl)(iodo)zinc in THF (0.5M, 9 ml) thenstirred at room temperature for 2 h. The reaction mixture was treatedwith aqueous ammonium chloride (1M) and diluted with ethyl acetate. Theorganic layer was separated using a hydrophobic filter tube and thesolvent was evaporated. The residue was purified by columnchromatography on silica (100 g) eluting with cyclohexane/ethyl acetate(100:0 to 0:100) to give the title compound (180 mg).

LC-MS: Rt 3.03 min MH⁺280/282.

Intermediate 33 6-Bromo-3-(2-pyridinyl)-1H-indazole

A mixture of (4-bromo-2-fluorophenyl)(2-pyridinyl)methanone(Intermediate 32, 180 mg) in methanol (3 ml) was treated with1,1-dimethylethyl hydrazinecarboxylate (169 mg) and acetic acid (0.1 ml)then heated at reflux for 16 h. The reaction mixture was partitionedbetween chloroform and saturated aqueous sodium hydrogen carbonate andthe organic layer was concentrated under vacuum. The residue and1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 ml) in THF (4.5 ml) in a sealedtube was heated at 150° C. in a microwave oven for 30 min. The reactionmixture was evaporated and the residue was purified by columnchromatography on silica eluting with cyclohexane/ethyl acetate (100:0to 0:100) to give the title compound (74 mg) as a white solid.

LC-MS: Rt 3.48 min, MH⁺274/276.

Intermediate 34N-(1-Ethyl-1H-pyrazol-5-yl)-3-fluoro-5-iodo-4-methylbenzamide

3-Fluoro-5-iodo-4-methylbenzoic acid (Intermediate 69, 6.27 g) inthionyl chloride (10 ml) was heated at 110° C. for 2.5 h. The mixturewas left to cool to room temperature overnight and the excess thionylchloride was removed under vacuum. Potassium carbonate (1.81 g) wasadded to a solution of the acid chloride (2.33 g) in dichloromethane (10ml). A solution of 5-amino-1-ethylpyrazole (1.29 g) in dichloromethane(5 ml) was added and the mixture was stirred overnight at roomtemperature. The solvent was removed under vacuum and the residue waswashed with water. The resulting solid was triturated with cyclohexaneand ether to give the title compound as a cream solid (1.48 g).

LCMS: Rt 3.18 min, MH+374.

Intermediate 35N-(1-Ethyl-1H-pyrazol-5-yl)-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

N-(1-Ethyl-1H-pyrazol-5-yl)-3-fluoro-5-iodo-4-methylbenzamide(Intermediate 34, 1.26 g), bispinnacolatodiborane (2.59 g), Pd(dppf)Cl₂(50 mg) and potassium acetate (1.01 g) in DMF (34 ml) was heated bymicrowave in a sealed vessel at 150° C. for 15 min. The reaction mixturewas absorbed onto silica and applied to a silica column (100 g). Elutionwith an ethyl acetate/cyclohexane gradient gave the title compound (850mg) as a yellow oil.

LCMS: Rt 3.36 min, MH+374.

Intermediate 36(4-Bromo-2-fluorophenyl)(1,3-dimethyl-1H-pyrazol-5-yl)methanone

A mixture of (4-bromo-2-fluorophenyl)(iodo)zinc in tetrahydrofuran(0.5M, 3 mL), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (238 mg) andtetrakis(triphenylphosphine)palladium(0) (87 g) in tetrahydrofuran (3mL) was stirred at room temperature under nitrogen for 1 h. Aqueousammonium chloride (1M, 5 mL) was added to the reaction mixture which wasthen extracted with ethyl acetate. The organic layer was washed withwater, dried using a hydrophobic filter tube and concentrated undervacuum. The residue was purified by chromatography on a silica column,eluting with a cyclohexane/ethyl acetate gradient, to give the titlecompound (324 mg).

LC-MS: Rt 3.16 min.

Intermediate 37 1,1-Dimethylethyl2-[(4-bromo-2-fluorophenyl)(1,3-dimethyl-1H-pyrazol-5-yl)methylidene]hydrazinecarboxylate

A mixture of(4-bromo-2-fluorophenyl)(1,3-dimethyl-1H-pyrazol-5-yl)methanone(Intermediate 36, 324 mg) and 1,1-dimethylethyl hydrazinecarboxylate(216 mg) in acetic acid (1 mL) and methanol (5 mL) was stirred at refluxunder nitrogen for 20 h. The solvent was removed under vacuum and theresidue was partitioned between ethyl acetate and aqueous sodiumhydrogen carbonate (1M). The organic phase was dried using a hydrophobicfilter tube and concentrated under vacuum. The residue was purified bychromatography on a silica column, eluting with a cyclohexane/ethylacetate gradient, to give the title compound (110 mg).

LC-MS: Rt 3.32 min.

Intermediate 38 6-Bromo-3-(1,3-dimethyl-1H-pyrazol-5-yl)-1H-indazole

A mixture of 1,1-dimethylethyl2-[(4-bromo-2-fluorophenyl)(1,3-dimethyl-1H-pyrazol-5-yl)methylidene]hydrazinecarboxylate(intermediate 37, 103 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (37 μL)in tetrahydrofuran (2.5 mL) in a sealed vial was heated at 150° C. for25 min in a microwave oven. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was dried using a hydrophobicfilter tube and concentrated under vacuum. The residue was purified bychromatography on a silica column, eluting with a cyclohexane/ethylacetate gradient, to give the title compound as a colourless glass (34mg).

LC-MS: Rt 3.26 min.

Intermediate 393-Fluoro-5-iodo-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide

3-Fluoro-5-iodo-4-methylbenzoic acid (Intermediate 69, 6.27 g) inthionyl chloride (10 ml) was heated at 110° C. for 2.5 h. The reactionwas left to cool to room temperature overnight and the excess thionylchloride was removed under vacuum. A portion (2.18 g) of the crude acidchloride in dichloromethane (10 ml) was treated with potassium carbonate(1.7 g) followed by a solution of 5-amino-1-methylpyrazole (0.94 g) indichloromethane (10 ml). The mixture was stirred overnight thenconcentrated under vacuum. The residue was washed with water thentriturated triturated with cyclohexane to give the title compound as acream solid (1.44 g).

LC-MS: Rt 3.08 min, MH+360.

Intermediate 403-Fluoro-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

3-Fluoro-5-iodo-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide(Intermediate 23, 1.44 g) bispinnacolatodiborane (3.05 g) Pd(dppf)Cl2(59 mg) and potassium acetate (1.19 g) were combined in DMF (34 ml),divided between 2 vials then heated by microwave in sealed vessels at150° C. for 15 min. The mixtures were combined, absorbed onto silica andapplied to silica columns (2×100 g). The columns were eluted with anethyl acetate/cyclohexane gradient to give the title compound as anoff-white solid (217 mg).

LC-MS: Rt 3.25 min, MH+360.

Intermediate 41 3-Fluoro-5-iodo-4-methyl-N−1H-pyrazol-5-ylbenzamide

N,N-Diisopropylethlamine (3.8 ml) and HATU (3.32 g) were added to asolution of 3-fluoro-5-iodo-4-methylbenzoic acid (Intermediate 69, 2.07g) in DMF (80 ml) and the reaction mixture was stirred for 10 min atroom temperature. 3-Aminopyrazole (0.9 ml) was added and stirring wascontinued at room temperature overnight. The reaction mixture wasabsorbed onto silica, applied to a silica column (100 g) and eluted withan ethyl acetate/cyclohexane gradient to give the title compound as apale yellow solid (555 mg).

LC-MS: Rt 3.07 min, MH+346.

Intermediate 423-Fluoro-4-methyl-N-1H-pyrazol-5-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

A mixture of 3-fluoro-5-iodo-4-methyl-N-1H-pyrazol-5-ylbenzamide (500mg), bispinnacolatodiborane (1.10 g) Pd(dppf)Cl₂ (27.4 mg) and potassiumacetate (462 mg) in DMF (13 ml) in a sealed vessel was at 150° C. in amicrowave oven for 15 min. The reaction mixture was absorbed onto silicaand applied to a silica column (100 g). Elution with an ethylacetate/cyclohexane gradient gave the title compound as a brown foam(288 mg).

LC-MS: Rt 3.21 min, MH+346.

Intermediate 43(4-Bromo-2-fluorophenyl)[6-(4-morpholinyl)-3-pyridinyl]methanone

A mixture of (4-bromo-2-fluorophenyl)(iodo)zinc in tetrahydrofuran(0.5M, 3 mL), 6-(4-morpholinyl)-3-pyridinecarbonyl chloride (340 mg) andtetrakis(triphenylphosphine)palladium(0) (87 g) in tetrahydrofuran (3mL) was stirred at room temperature under nitrogen for 1 h. Aqueousammonium chloride (1M, 5 mL) was added and the mixture was extractedwith ethyl acetate. The organic phase was washed with water, dried usinga hydrophobic filter tube and concentrated under vacuum. The residue waspurified by chromatography on a silica column, eluting with acyclohexane/ethyl acetate gradient, to give the title compound (282 mg).

LC-MS: Rt 3.16 min.

Intermediate 44 1,1-Dimethylethyl2-{(4-bromo-2-fluorophenyl)[6-(4-morpholinyl)-3-pyridinyl]methylidene}hydrazinecarboxylate

A mixture of(4-bromo-2-fluorophenyl)[6-(4-morpholinyl)-3-pyridinyl]methanone(Intermediate 43, 282 mg) and 1,1-dimethylethyl hydrazinecarboxylate(152 mg) in acetic acid (1 mL) and methanol (5 mL) was stirred at refluxunder nitrogen for 20 h. The solvent was removed under vacuum and theresidue was partitioned between ethyl acetate and aqueous sodiumhydrogen carbonate (1M). The organic phase was dried using a hydrophobicfilter tube and concentrated under vacuum. The residue was purified bychromatography on a silica column, eluting with a cyclohexane/ethylacetate gradient to give the title compound (235 mg).

LC-MS: Rt 3.28 min.

Intermediate 45 6-Bromo-3-[6-(4-morpholinyl)-3-pyridinyl]-1H-indazole

A mixture of 1,1-dimethylethyl2-{(4-bromo-2-fluorophenyl)[6-(4-morpholinyl)-3-pyridinyl]methylidene}hydrazinecarboxylate(Intermediate 44, 235 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (73 μL)in tetrahydrofuran (2.5 mL) in a sealed vial was heated at 150° C. for25 min in a microwave oven. The reaction mixture was partitioned betweenethyl acetate and water and the organic layer was dried using ahydrophobic filter tube and concentrated under vacuum. The residue waspurified by chromatography on a silica column, eluting with acyclohexane/ethyl acetate gradient, to give the title compound as ayellow solid (70 mg).

LC-MS: Rt 3.28 min.

Intermediate 46 (4-Bromo-2-fluorophenyl)(2-pyrimidinyl)methanone

2-Pyrimidinecarboxylic acid (350 mg) in thionyl chloride (3 mL) wasstirred at 110° C. under nitrogen for 1.5 h. The solvent was removedunder vacuum to give the 2-pyrimidinecarbonyl chloride as a grey solid(403 mg). (4-Bromo-2-fluorophenyl)(iodo)zinc in tetrahydrofuran (0.5M,5.65 mL) was added slowly to a stirred mixture of the acid chloride (403mg) and tetrakis(triphenylphosphine)palladium(0) (163 mg) intetrahydrofuran (3 mL) at room temperature under nitrogen. The reactionmixture was stirred at room temperature under nitrogen for 1 h andaqueous ammonium chloride (1M, 6 mL) was added. The mixture was absorbedonto silica and purified by chromatography on a silica column, elutingwith a cyclohexane/ethyl acetate gradient to give the title compound(257 mg).

LC-MS: Rt 2.95 min.

Intermediate 47 1,1-Dimethylethyl2-[(4-bromo-2-fluorophenyl)(2-pyrimidinyl)methylidene]hydrazinecarboxylate

A mixture of (4-bromo-2-fluorophenyl)(2-pyrimidinyl)methanone(Intermediate 46, 257 mg) and 1,1-dimethylethyl hydrazinecarboxylate(241 mg) in acetic acid (1 mL) and methanol (5 mL) was stirred at refluxunder nitrogen for 20 h. The solvent was removed under vacuum and theresidue was partitioned between ethyl acetate and water. The organicphase was washed with aqueous sodium hydrogen carbonate (1M), driedusing a hydrophobic filter tube and concentrated under vacuum. Theresidue was purified by chromatography on a silica column, eluting witha cyclohexane/ethyl acetate gradient to give the title compound as awhite solid (73 mg).

LC-MS: Rt 3.08 min.

Intermediate 48 6-Bromo-3-(2-pyrimidinyl)-1H-indazole

A mixture of 1,1-dimethylethyl2-[(4-bromo-2-fluorophenyl)(2-pyrimidinyl)methylidene]hydrazinecarboxylate(Intermediate 47, 73 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (28 uL)in tetrahydrofuran (2.5 mL) in a sealed vial was heated at 150° C. for25 min in a microwave oven. The reaction mixture was partitioned betweenethyl acetate and water, the organic layer was dried using a hydrophobicfilter tube and the solvent was removed under vacuum. The residue waspurified by chromatography on a silica column, eluting with acyclohexane/ethyl acetate gradient to give the title compound as a whitesolid (17 mg).

LC-MS: Rt 3.17 min.

Intermediate 49 (4-Bromo-2-fluorophenyl)(5-pyrimidinyl)methanone

5-Pyrimidinecarboxylic acid (500 mg) in thionyl chloride (5 mL) wasstirred at 110° C. under nitrogen for 1 h. The solvent was evaporatedunder vacuum to give 5-pyrimidinecarbonyl chloride as a brown oil (505mg). (4-Bromo-2-fluorophenyl)(iodo)zinc in tetrahydrofuran (0.5M, 7.0mL) was added slowly to a stirred mixture of the acid chloride (500 mg)and tetrakis(triphenylphosphine)palladium(0) (203 mg) in tetrahydrofuran(3 mL) at room temperature under nitrogen then stirred at roomtemperature for 1 h. Aqueous ammonium chloride (1M, 5 mL) was added andthe mixture was absorbed onto silica and purified by chromatography on asilica column eluting with a cyclohexane/ethyl acetate gradient to givethe title compound (712 mg).

LC-MS: Rt 2.65 min.

Intermediate 50 1,1-Dimethylethyl2-[(4-bromo-2-fluorophenyl)(5-pyrimidinyl)methylidene]hydrazinecarboxylate

A mixture of (4-bromo-2-fluorophenyl)(5-pyrimidinyl)methanone(Intermediate 49, 712 mg) and 1,1-dimethylethyl hydrazinecarboxylate(502 mg) in acetic acid (1 mL) and methanol (10 mL) was stirred atreflux under nitrogen for 30 h. More 1,1-dimethylethylhydrazinecarboxylate (502 mg) was added and the reaction mixture wasstirred at reflux for a further 14 h. The solvent was removed undervacuum and the residue was partitioned between ethyl acetate and sodiumbicarbonate (1M). The organic phase was dried using a hydrophobic filtertube and concentrated under vacuum. The residue was purified bychromatography on a silica column, eluting with a cyclohexane/ethylacetate gradient, to give the title compound (531 mg).

LC-MS: Rt 3.08 min.

Intermediate 51 6-Bromo-3-(5-pyrimidinyl)-1H-indazole

A mixture of 1,1-dimethylethyl2-[(4-bromo-2-fluorophenyl)(5-pyrimidinyl)methylidene]hydrazinecarboxylate(Intermediate 50, 531 mg) and 1,8-diazabicyclo[5.4:0]undec-7-ene (200μL) in tetrahydrofuran (4 mL) in a sealed vessel was heated at 150° C.for 25 min in a microwave oven. The reaction mixture was partitionedbetween ethyl acetate and water and the organic layer was dried using ahydrophobic filter tube and concentrated under vacuum. The residue waspurified by chromatography on a silica column eluting with acyclohexane/ethyl acetate gradient, to give the title compound as awhite solid (120 mg).

LC-MS: Rt 2.85 min.

Intermediate 52 (4-bromo-2-fluorophenyl)(2-pyrazinyl)methanone

2-Pyrazinecarboxylic acid (1.5 g) in thionyl chloride (10 mL) wasstirred at 110° C. under nitrogen for 2 h. The solvent was evaporatedunder vacuum to give 2-pyrazinecarbonyl chloride as a dark purple solid(1.5 g). (4-Bromo-2-fluorophenyl)(iodo)zinc in tetrahydrofuran (0.5M,7.02 mL) was added slowly to a stirred mixture of the acid chloride (1g) and tetrakis(triphenylphosphine)palladium(0) (406 mg) intetrahydrofuran (5 mL) at room temperature under nitrogen then stirredfor 2 h. Aqueous ammonium chloride (1M, 10 mL) was added and thereaction mixture was partitioned between ethyl acetate and water. Theorganic phase was dried using a hydrophobic filter tube and concentratedunder vacuum. The residue was purified by chromatography on a silicacolumn eluting with a cyclohexane:ethyl acetate gradient to give thetitle compound as a yellow solid (215 mg).

LC-MS: Rt 2.83 min.

Intermediate 53 1,1-Dimethylethyl2-[(4-bromo-2-fluorophenyl)(2-pyrazinyl)methylidene]hydrazinecarboxylate

A mixture of (4-bromo-2-fluorophenyl)(2-pyrazinyl)methanone(Intermediate 52, 215 mg) and 1,1-dimethylethyl hydrazinecarboxylate(152 mg) in acetic acid (131 μL) and methanol (10 mL) was stirred atreflux under nitrogen for 20 h. The solvent was removed under vacuum andthe residue was partitioned between chloroform:ethyl acetate (1:1) andwater. The organic phase was dried using a hydrophobic filter tube andconcentrated under vacuum to give impure title compound as a brown oil(352 mg).

LC-MS: Rt 3.2 min.

Intermediate 54 6-bromo-3-(2-pyrazinyl)-1H-indazole

A mixture of impure 1,1-dimethylethyl2-[(4-bromo-2-fluorophenyl)(2-pyrazinyl)methylidene]hydrazinecarboxylate(Intermediate 52, 352 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (133uL) in tetrahydrofuran (5 mL) in a sealed vial was heated at 150° C. for30 min in a microwave oven. The reaction mixture was partitioned betweenethyl acetate and water and the organic phase was dried using ahydrophobic filter tube and concentrated under vacuum. The residue waspurified by chromatography on a silica column, eluting with acyclohexane/ethyl acetate gradient, to give the title compound as awhite solid (115 mg).

LC-MS: Rt 3.33 min.

Intermediate 553-(3-Bromo-1H-indazol-6-yl)-N-ethyl-5-fluoro-4-methylbenzamide

N-Bromosuccinimide (0.992 g) was added to a solution ofN-ethyl-3-fluoro-5-(1H-indazol-6-yl)-4-methylbenzamide (Intermediate 27,1.4 g) in THF (15 ml) and stirred at 60° C. under nitrogen. The reactionmixture was allowed to cool to room temperature and the solvent wasevaporated under vacuum. The crude material was purified by columnchromatography on silica eluting with a cyclohexane/ethyl acetategradient to give the title compound as a yellow powder (0.92 g).

LC-MS: Rt 3.33 min, MH⁺376.

Intermediate 56 Methyl6-[(4-bromo-2-fluorophenyl)carbonyl]-3-pyridinecarboxylate

5-[(Methyloxy)carbonyl]-2-pyridinecarboxylic acid (1 g) in thionylchloride (10 mL) was stirred at 110° C. under nitrogen for 1 h. Excessthionyl chloride was removed under vacuum to give the methyl6-(chlorocarbonyl)-3-pyridinecarboxylate as a white solid (1.05 g).(4-Bromo-2-fluorophenyl)(iodo)zinc in tetrahydrofuran (0.5M, 10 mL) wasadded slowly to a stirred mixture of the acid chloride (1 g) andtetrakis(triphenylphosphine)palladium(0) (290 mg) in tetrahydrofuran (5mL) at room temperature under nitrogen, stirred for 5 h then treatedwith aqueous ammonium chloride (1M, 10 mL). The mixture was absorbedonto silica and purified by chromatography on a silica column elutingwith a cyclohexane/ethyl acetate gradient to give the title compound(635 mg).

LC-MS: Rt 3.37 min.

Intermediate 576-({5′-[(Ethylamino)carbonyl]-3-fluoro-2′-methyl-4-biphenylyl}carbonyl)-3-pyridinecarboxylicacid

A mixture of 6-[(4-bromo-2-fluorophenyl)carbonyl]-3-pyridinecarboxylate(Intermediate 56, 500 mg),N-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 18, 428 mg), aqueous sodium hydrogen carbonate (2.96 mL)and tetrakis(triphenylphosphine)palladium(0) (34 mg) in isopropanol (15ml) in a sealed vial was stirred at 150° C. for 20 min in a microwaveoven. Saturated aqueous citric acid (5 mL) was added, the solvent wasremoved under vacuum and the residue was purified by chromatography on asilica column eluting with a cyclohexane/ethyl acetate gradient to givethe title compound (460 mg).

LC-MS: Rt 3.27 min.

Intermediate 58N-Ethyl-6-({5′-[(ethylamino)carbonyl]-3-fluoro-2′-methyl-4-biphenylyl}carbonyl)-3-pyridinecarboxamide

Ethylamine 2M in tetrahydrofuran (276 μL) was added to a mixture of6-({5′-[(ethylamino)carbonyl]-3-fluoro-2′-methyl-4-biphenylyl}carbonyl)-3-pyridinecarboxylicacid (Intermediate 57, 150 mg),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (106 mg),and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (5 mg) in chloroform (20 mL)at room temperature under nitrogen then stirred for 2 h. The mixture waswashed with water (20 mL) dried dried using a hydrophobic filter tubeand concentrated under vacuum. The residue was purified bychromatography on a silica column eluting with a cyclohexane/ethylacetate gradient to give the title compound (98 mg).

LC-MS: Rt 3.01 min.

Intermediate 59 1,1-Dimethylethyl2-({5′-[(ethylamino)carbonyl]-3-fluoro-2′-methyl-4-biphenylyl}{5-[(ethylamino)carbonyl]-2-pyridinyl}methylidene)hydrazinecarboxylate

A mixture ofN-ethyl-6-({5′-[(ethylamino)carbonyl]-3-fluoro-2′-methyl-4-biphenylyl}carbonyl)-3-pyridinecarboxamide(Intermediate 58, 98 mg), 1,1-dimethylethyl hydrazinecarboxylate (45 mg)and acetic acid (39 uL) in methanol (5 mL) was stirred at reflux undernitrogen for 60 h. The solvent was removed under vacuum and the residuewas partitioned between ethyl acetate and water. The organic phase wasdried using a hydrophobic filter tube and concentrated under vacuum togive impure title compound as a yellow oil (198 mg).

LC-MS: Rt 3.17 min.

Intermediate 603-Fluoro-5-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzoic acid

A mixture of methyl3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(Intermediate 8, 709 mg), 6-bromo-3-(4-fluorophenyl)-1H-indazole(Intermediate 20, 707 mg), aqueous sodium hydrogen carbonate (1M, 7.2ml) and tetrakis(triphenylphosphine)palladium (61 mg) in propan-2-ol (10ml) in a sealed vessel was heated in a microwave oven at 150° C. for 15min. Two further portions of aqueous sodium hydrogen carbonate (1M, 2.4ml) were added over 3d and the mixture was stirred at room temperature.The reaction was then heated at 50° C. for 2 h, the solvent was removedunder vacuum and the residue was partitioned between ethyl acetate andwater. The organic phase was concentrated under vacuum, methanol (15 ml)and aqueous sodium hydroxide (2M, 10 ml) were added and the mixture wasstirred at room temperature overnight. The solvent was evaporated andthe residue was partitioned between ethyl acetate and sodium hydroxide(2M) then filtered. The aqueous phase was acidified with hydrochloricacid (2M) and the precipitate collected by filtration and dried to givethe title compound as a yellow solid (166 mg).

LC-MS: Rt 3.92 min, MH+365.

Intermediate 61N-(1,4-Dimethyl-1H-pyrazol-5-yl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(507 mg) was dissolved in DMF (5 ml). An aliquot (1 ml) was treated withDIPEA (0.2 ml) and HATU (181 mg) the mixture was stirred for 10 min atroom temperature. 1,4-Dimethyl-1H-pyrazol-5-amine (72 mg) was added andthe mixture was stirred at room temperature overnight. The solvent wasevaporated under a stream of nitrogen and the residue was absorbed ontosilica and purified by chromatography on a silica column eluting withcyclohexane/ethyl acetate (1:1 to give the title compound as a whitesolid (121 mg).

LCMS: Rt 3.26 min, MH+356.

Intermediate 62N-(3,5-Dimethyl-4-isoxazolyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(507 mg) was dissolved in DMF (5 ml). An aliquot (1 ml) was treated withDIPEA (0.2 ml) and HATU (180 mg) and the mixture was stirred for 10 minat room temperature. 3,5-Dimethyl-4-isoxazolamine (65 mg) was added andthe mixture was stirred at room temperature overnight. The DMF wasremoved under a stream of nitrogen and the residue absorbed onto silicaand purified by chromatography on a silica column eluting withcyclohexane/ethyl acetate (7:3). The resultant was tritureated withether to give the title compound as a white solid (41 mg).

LCMS: Rt 3.31 min, MH+357.

Intermediate 63 1,1-Dimethylethyl 3-fluoro-5-iodo-4-methylbenzoate

Carbonyl diimidazole (12.9 g) was added to a stirred solution of3-fluoro-5-iodo-4-methylbenzoic acid (Intermediate 69, 15 g) in DMF (200ml) at 40° C. After 40 min tert-butanol (8.0 ml) and1,8-diazobicyclo[5,4,0]undec-7-ene (8.1 ml) were added and the solutionwas stirred for 18 h at 40° C. The reaction was poured into water (1000ml) and the precipitate collected by filtration to give the titlecompound as a pale brown solid (15.4 g).

LC-MS: Rt 4.08 min.

Intermediate 64 6-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indazole

A stirred mixture of 6-bromoindazole (5 g), bisneopentylglycolato-diboron (6.9 g), potassium acetate (3.0 g) and Pd(dppf) (0.5g) in DMSO (500 ml) was heated at 80° C. for 5.5 h under nitrogen. Themixture was poured into water (1500 ml) and extracted into ethyl acetate(4×200 ml). The combined extracts were washed with water (500 ml), thenconcentrated under vacuum The residue was purified by columnchromatography on silica eluting with an ethyl acetate/cyclohexanegradient (10:90 to 100:0) to give the title compound as a brown solid.(8.4 g).

LC-MS: Rt 1.92 min.

Intermediate 65 1,1-Dimethylethyl3-fluoro-5-(1H-indazol-6-yl)-4-methylbenzoate

A mixture of 1,1-dimethylethyl 3-fluoro-5-iodo-4-methylbenzoate(Intermediate 63, 3.42 g),6-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indazole (Intermediate 64,2.81 g), aqueous sodium hydrogen carbonate (1M, 7.5 ml) andtetrakis(triphenylphosphine)palladium(0) (120 mg) in isopropanol (30 ml)was stirred at relux under nitrogen for 20 h. Water and ethyl acetatewere added, the phases were separated and the aqueous layer wasre-extracted with ethyl acetate. The solvent was evaporated and theresidue was purified by column chromatography on silica eluting with acyclohexane/ethyl acetate gradient to give the title compound as ayellow solid (1.6 g).

LC-MS: Rt 3.78 min.

Intermediate 66 1,1-Dimethylethyl3-fluoro-5-(3-iodo-1H-indazol-6-yl)-4-methylbenzoate

Iodine (1 g) was added to a stirred solution of 1,1-dimethylethyl3-fluoro-5-(1H-indazol-6-yl)-4-methylbenzoate (Intermediate 65, 1.1 g)in 1,4-dioxan (15 ml) and 2M sodium hydroxide solution (5 ml). After 2 hthe mixture was treated with aqueous sodium bisulphite (10%, 30 ml) andaqueous citric acid (10%, 30 ml). The mixture was extracted withdichloromethane (3×25 ml) and the combined organic extracts were washedwith water (30 ml), dried (Na₂SO₄) and concentrated under vacuum to givethe title compound as a pale orange foam (1.4 g).

LC-MS: Rt 4.22 min, MH+453.

Intermediate 67 1,1-Dimethylethyl3-fluoro-5-[3-iodo-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indazol-6-yl]-4-methylbenzoate

2-(Trimethylsilyl)ethoxymethyl chloride (0.67 g) was added to anice-bath cooled mixture of 1,1-dimethylethyl3-fluoro-5-(3-iodo-1H-indazol-6-yl)-4-methylbenzoate (Intermediate 66,1.5 g), tetra-butylammonium bromide (0.2 g) and aqueous potassiumhydroxide (50%, 15 ml) in dichloromethane (20 ml). The mixture wasstirred for 10 min, poured into water (50 ml) and extracted intodichloromethane (3×30 ml). The combined extracts were washed with water(50 ml), dried (Na₂SO₄) and concentrated under vacuum. The residual oilwas purified by column chromatography on silica eluting withether/cyclohexane (1:9) to give the title compound as an orange oil (1.9g).

LC-MS: Rt 4.46 min MH+583.

Intermediate 68 1,1-Dimethylethyl3-[3-(1,2-dimethyl-1H-imidazol-5-yl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indazol-6-yl]-5-fluoro-4-methylbenzoate

A mixture of 1,1-dimethylethyl3-fluoro-5-[3-iodo-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indazol-6-yl]-4-methylbenzoate(Intermediate 67, 0.1 g),1,2-dimethyl-5-(tributylstannanyl)-1H-imidazole (0.15 g) andtetrakis(triphenylphosphine)palladium(0) (0.03 g) in toluene (1 ml) washeated at 120° C. for 30 min in a microwave oven. The solvent wasevaporated and the residue was purified by preparative HPLC to give thetitle compound as a pale green oil (0.09 g).

LC-MS: Rt 3.47 min, MH+551.

Intermediate 69 3-Fluoro-5-iodo-4-methylbenzoic acid

A solution of 3-fluoro-4-methylbenzoic acid (149.7 g) intrifluoromethanesulphonic acid (1050 ml) at −22° C. under nitrogen wastreated portionwise over 1.25 h with iodosuccinimide (203.5 g). Themixture was stirred at −20° C. for and further portions ofiodosuccinimide were added after 2.5 h (46.5 g) and 20.5 h (30 g). Themixture was stirred at −20° C. for a further 24 h then added slowly to amixture of aqueous sodium thiosulphate (10%, 1.5 L) and ice (3 kg). Theresultant precipitate was collected by filtration and stirred with ethylacetate (5 L) and aqueous sodium thiosulphate (10%, 1.5 L). The organicphase was dried (MgSO₄) and concentrated to ˜1.5 L then left overnight.The precipitate was collected by filtration and further material wasobtained through concentration of the filtrate to give the titlecompound as a white solid (133.9 g).

LC-MS: Rt 3.60, MH+281.

Example 1N-Cyclopropyl-3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide

A mixture of 5-bromo-1-phenyl-1H-indazole (Intermediate 1, 34.6 mg),{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (30mg), tetrakis(triphenylphosphine) palladium (3 mg) and aqueous sodiumhydrogen carbonate (1M, 0.63 ml) in isopropanol (2 ml) in a sealedvessel was heated in a microwave oven at 150° C. for 10 min (70W). Thereaction mixture was filtered, the solvents were removed under vacuumand the residue was purified by preparative HPLC to give the titlecompound (32 mg).

LC-MS: Rt 3.54 min, MH+386.

Example 2N-Cyclopropyl-3-fluoro-5-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methylbenzamide

The procedure for Example 1 was followed using5-bromo-1-(4-fluorophenyl)-1H-indazole (Intermediate 2, 36.6 mg),{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (30mg), tetrakis(triphenylphosphine) palladium (3 mg) and aqueous sodiumhydrogen carbonate (1M, 0.63 ml) in isopropanol (2 ml) tog ive the titlecompound (30.7 mg).

LC-MS: Rt 3.56 min, MH+404.

Example 3N-Cyclopropyl-3-fluoro-5-[1-(4-fluoro-2-methylphenyl)-1H-indazol-5-yl]-4-methylbenzamide

A mixture ofN-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide(Intermediate 5, 31 mg), (4-fluoro-2-methylphenyl)boronic acid (31 mg),anhydrous copper (II) acetate (27 mg), pyridine (16.4 μl) and 4Apowdered molecular sieves (75 mg) in dichloromethane (2 ml) was stirredat room temperature for 24 h. Further dichloromethane (1 ml) was addedand after 24 h the reaction mixture was diluted with chloroform (3 ml)and water (3 ml). The organic phase was separated using a hydrophobicfilter tube and the solvent was evaporated. The residue was purified bypreparative HPLC to give the title compound as a yellow gum (10.5 mg).

LC-MS: Rt 3.63 min, MH+418.

Example 4N-Cyclopropyl-3-fluoro-5-{1-[(4-fluorophenyl)methyl]-1H-indazol-5-yl}-4-methylbenzamide

A solution ofN-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide(Intermediate 5, 31 mg) and sodium hydride (60% dispersion in mineraloil, 4 mg) in DMF (1.6 ml) was stirred at room temperature undernitrogen. After 1 hour, 1-(bromomethyl)-4-fluorobenzene (15 μl) wasadded and the resulting mixture was allowed to stir under nitrogen atroom temperature. After 1 h, ammonia (aqueous 0.88, 200 μl) was addedand the resulting mixture was allowed to stir under nitrogen at roomtemperature. After 1 h, the mixture was concentrated. The residue waspurified by preparative HPLC to give the title compound (7 mg).

LC-MS: Rt 3.49, MH⁺418.

Example 5N-Cyclopropyl-3-fluoro-4-methyl-5-(1-{[4-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)benzamide

The procedure for Example 4 was followed usingN-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide(Intermediate 5, 31 mg), sodium hydride (60% dispersion in mineral oil,4 mg), 1-(bromomethyl)-4-(trifluoromethyl)benzene (19 μL) and DMF (1.6ml) to give the title compound (6 mg).

LC-MS: Rt 3.65, MH⁺468.

Example 6N-Cyclopropyl-3-fluoro-4-methyl-5-[1-(phenylmethyl)-1H-indazol-5-yl]benzamide

The procedure for Example 4 was followed usingN-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide(Intermediate 5, 31 mg), sodium hydride (60% dispersion in mineral oil,4 mg), (bromomethyl)benzene (14 μl) and DMF (1.6 ml) to give the titlecompound (9 mg).

LC-MS: Rt 3.48, MH⁺400.

Example 7N-Cyclopropyl-3-fluoro-4-methyl-5-{1-[(5-methyl-3-isoxazolyl)methyl]-1H-indazol-5-yl}benzamide

Sodium hydride (60% in mineral oil, 12 mg) was added toN-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide(Intermediate 5, 45 mg) in DMF (5 ml) and the mixture was stirred atroom temperature for 1 h. 3-(Bromomethyl)-5-methylisoxazole (28.2 mg)was added and stirring was continued for 18 h. The mixture was dilutedwith chloroform/ethyl acetate (1:1, 5 ml) and washed with water (2×5ml). The organic phase was concentrated under vacuum and the residue waspurified on a silica column eluting with chloroform/ethyl acetate (9:1)to give the title compound as a colourless glass (10 mg).

LC-MS: Rt 3.14 min, MH+405.

Example 8N-Cyclopropyl-3-fluoro-4-methyl-5-[1-2-pyridinylmethyl)-1H-indazol-5-yl]benzamide

The procedure for Example 7 was followed usingN-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide(Intermediate 5, 45 mg), sodium hydride (60% in mineral oil, 18 mg),2-(bromomethyl)pyridine (40 mg) and DMF (5 ml) to give the titlecompound as a colourless glass (10 mg).

LC-MS: Rt 3.07 min, MH+401.

Example 9N-Cyclopropyl-3-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methylbenzamide

A mixture of 5-bromo-1-(4-fluorophenyl)-1H-indazole (Intermediate 2, 29mg),N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(30 mg), tetrakis(triphenylphoshine)palladium (0) (6 mg) and 1M aqueoussodium bicarbonate (1 ml) in 2-propanol (1 ml) was heated at 150° C. for15mins in a microwave oven. The reaction mixture was diluted withchloroform and the organic layer was separated using a hydrophobicfilter tube. The organic layer was evaporated and the residue waspurified on an SPE cartridge (silica) using a petroleum ether/ethylacetate gradient to give the title compound as a colourless gum (34 mg).

LC-MS: Rt 3.50 min MH+386.

Example 10N-Cyclobutyl-3-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methylbenzamide

A mixture of 5-bromo-1-(4-fluorophenyl)-1H-indazole (Intermediate 2, 29mg),N-cyclobutyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 6, 32 mg), tetrakis(triphenylphoshine)palladium (0) (6mg)) and 1M aqueous sodium bicarbonate in 2-propanol (1 ml) was heatedat 150° C. for 15 min in a microwave oven. The reaction mixture wasdiluted with chloroform and the organic layer separated using ahydrophobic filter tube. The organic layer was evaporated and theresidue was purified on an SPE cartridge (silica) eluting with apetroleum ether/ethyl acetate gradient to give the title compound as acolourless gum (34 mg).

LC-MS: Rt 3.66 min, MH+400.

Example 11N-Cyclopropyl-3-fluoro-4-methyl-5-{1-[4-(4-morpholinyl)phenyl]-1H-indazol-5-yl}benzamide,formate salt

A mixture ofN-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide(Intermediate 5, 80 mg), [4-(4-morpholinyl)phenyl]boronic acid (105 mg),anhydrous copper (II) acetate (71 mg), pyridine (40 μl) and 4A powderedmolecular sieves (200 mg) in dichloromethane (5 ml) was stirred at roomtemperature for 24 h. Further dichloromethane (1 ml) was added and after24 h the reaction mixture was diluted with chloroform (3 ml) and water(3 ml). The organic phase was separated using a hydrophobic filter tubeand the solvent was evaporated. The residue was purified by preparativeHPLC to give the title compound as an off-white solid (32 mg).

LC-MS: Rt 3.42 min, MH+471.

General Method 1

A mixture of 3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzoic acid(Intermediate 9, 70 mg) in thionyl chloride (3 ml) was stirred at refluxfor 30 min. Excess thionyl chloride was removed under vacuum and theresidue was a zeotroped with toluene to remove residual thionylchloride. The crude acid chloride was dissolved in chloroform (3.1 ml)and an aliquot (300 μl) was treated with an amine (50 μmol) inchloroform (1 ml). After 1 h the reaction mixture was diluted withchloroform and washed with 1M aqueous hydrochloric acid followed byaqueous sodium hydrogen carbonate. The organic layer was separated usinga hydrophobic filter tube then concentrated under vacuum to give thetitle compound.

Example 12 3-Fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide

The title compound (8.3 mg) was prepared by General Method 1 using asolution of ammonia in dioxan (0.5M).

LC-MS: Rt 3.43 min, MH+346.

Example 13 3-Fluoro-N,4-dimethyl-5-(1-phenyl-1H-indazol-5-yl)benzamide

The title compound (2.0 mg) was prepared by General Method 1 using asolution of methylamine in tetrahydrofuran (2M).

LC-MS: Rt 3.52 min, MH+360.

Example 14N-Ethyl-3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide

The title compound (5.9 mg) was prepared by General Method 1 using asolution of ethylamine in tetrahydrofuran (2M).

LC-MS: Rt 3.62 min, MH+374.

Example 153-Fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)-N-propylbenzamide

The title compound (6.4 mg) was prepared by General Method 1 usingpropylamine.

LC-MC: 3.73 min, MH+388.

Example 16N-Butyl-3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide

The title compound (4.6 mg) was prepared by General Method 1 usingbutylamine. LC-MS: Rt 3.86 min, MH+402.

Example 17N-Cyclobutyl-3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide

The title compound (6.6 mg) was prepared by General Method 1 usingcyclobutylamine.

LC-MS: Rt 3.77 min, MH+400.

Example 18N-Cyclopentyl-3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide

The title compound (6.5 mg) was prepared by General Method 1 usingcyclopentylamine.

LC-MS: Rt 3.84 min, MH+414.

Example 193-Fluoro-4-methyl-N-(1-methylethyl)-5-(1-phenyl-1H-indazol-5-yl)benzamide

The title compound (6.6 mg) was prepared by General Method 1 usingisopropylamine.

LC-MS: Rt 3.68 min, MH+388.

Example 20N-(Cyclopropylmethyl)-3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide

The title compound (6.5 mg) was prepared by General Method 1 usingcyclopropylmethylamine.

LC-MS: Rt 3.67 min, MH+400.

Example 21N-Cyclopropyl-3-fluoro-4-methyl-5-[1-(2-pyridinyl)-1H-indol-5-yl]benzamide

A suspension of and 5-bromo-1-(2-pyridinyl)-1H-indole (27 mg),{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (26mg), tetrakis(triphenylphosphine)palladium(0) (1 mg) and aqueous sodiumhydrogen carbonate (1M, 0.3 ml) in isopropanol (0.6 ml) was heated at150° C. in a microwave oven for 15 min. The mixture was partitionedbetween water and ethyl acetate and the organic layer was washed withwater and brine, dried using a hydrophobic filter tube and concentratedunder vacuum. The residue was purified by preparative HPLC to give thetitle compound (15 mg).

LC-MS: Rt 3.6, MH⁺386.

Example 22N-Cyclopropyl-3-fluoro-4-methyl-5-[1-(3-pyridinyl)-1H-indol-5-yl]benzamide

The procedure for Example 21 was followed using5-bromo-1-(3-pyridinyl)-1H-indole (27 mg),{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (26mg), tetrakis(triphenylphosphine)palladium (0) (1 mg) and aqueous sodiumhydrogen carbonate (1M, 0.3 ml) in isopropanol (0.6 ml) to give thetitle compound (18 mg).

LC-MS: Rt 3.31, MH⁺386.

Example 233-[1-(4-Cyanophenyl)-1H-indol-5-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide

The procedure for Example 21 was followed using4-(5-bromo-1H-indol-1-yl)benzonitrile (Intermediate 10, 30 mg),{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (26mg), tetrakis(triphenylphosphine)palladium (0) (1 mg) and aqueous sodiumhydrogen carbonate (1M, 0.3 ml) in isopropanol (0.6 ml) to give thetitle compound (2.7 mg).

LC-MS: Rt 3.64, MH⁺410.

Example 243-[1-(3-Cyanophenyl)-1H-indol-5-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide

The procedure for Example 21 was followed using3-(5-bromo-1H-indol-1-yl)benzonitrile (30 mg),{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (26mg), tetrakis(triphenylphosphine)palladium (0) (1 mg) and aqueous sodiumhydrogen carbonate (1M, 0.3 ml) in isopropanol (0.6 ml) to give thetitle compound (2.9 mg).

LC-MS: Rt 3.64, MH⁺410.

Example 25N-Cyclopropyl-3-fluoro-4-methyl-5-[1-(3-methylphenyl)-1H-indazol-5-yl]benzamide

A mixture of 5-bromo-1-(3-methylphenyl)-1H-indazole (Intermediate 11,179 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronicacid (173 mg), tetrakis(triphenylphosphine)palladium (18.7 mg) andaqueous sodium hydrogen carbonate (1M, 1 ml) in propan-2-ol (2.5 ml) washeated in a microwave oven at 150° C. for 10 min. The solvent wasevaporated and the residue was partitioned between chloroform and water.The organic phase was absorbed onto silica and purified on an SPEcartridge (silica) eluting with an cyclohexane/ethyl acetate gradient togive the title compound as a glass (153 mg).

LC-MS: Rt 3.73 min, MH+400.

Example 26N-Cyclopropyl-3-fluoro-4-methyl-5-{1-[4-(trifluoromethyl)phenyl]-1H-indazol-5-yl}benzamide

The procedure for Example 25 was followed using5-bromo-1-[4-(trifluoromethyl)phenyl]-1H-indazole (Intermediate 12, 202mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronicacid (167 mg), tetrakis(triphenylphosphine)palladium (13.8 mg) andaqueous sodium hydrogen carbonate (1M, 1.2 ml) in isopropanol (2.8 ml)to give the title compound (115 mg).

LC-MS: Rt 3.85 min, MH+454.

Example 27N-Cyclopropyl-3-fluoro-4-methyl-5-{1-[4-(methylsulfonyl)phenyl]-1H-indazol-5-yl}benzamide

The procedure for Example 25 was followed5-bromo-1-[4-(methylsulfonyl)phenyl]-1H-indazole (Intermediate 13, 210mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronicacid (167 mg), tetrakis(triphenylphosphine)palladium (13.8 mg) andaqueous sodium hydrogen carbonate (1M, 1.2 ml) in isopropanol (2.8 ml)to give the title compound as a pale yellow foam (156 mg).

LC-MS: Rt 3.28 min, MH+464.

Example 28N-Cyclopropyl-3-fluoro-4-methyl-5-(1-{4-[2-(methylamino)-2-oxoethyl]phenyl}-1H-indazol-5-yl)benzamide

The procedure for Example 25 was followed using2-[4-(5-bromo-1H-indazol-1-yl)phenyl]-N-methylacetamide (Intermediate15, 206 mg),{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid(167 mg), tetrakis(triphenylphosphine)palladium (13.8 mg) and aqueoussodium hydrogen carbonate (1M, 1.2 ml) in isopropanol (2.8 ml). Thesilica SPE cartridge was eluted with a chloroform/methanol gradient togive the title compound as a yellow oil (147 mg).

LC-MS: Rt 3.10 min, MH+457.

Example 293-[1-(4-Bromophenyl)-1H-indazol-5-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide

N-Cyclopropyl-4′,5-difluoro-3′-formyl-6-methyl-3-biphenylcarboxamide(Intermediate 16, 158 mg) and 4-bromophenylhydrazine (94 mg) werecombined in acetonitrile (3.1 ml) and the mixture was warmed until aprecipitate formed. The acetonitrile was removed under vacuum, theresidue was dissolved in DMSO (6.2 ml) and cesium carbonate (210 mg) wasadded. The mixture was heated at 150° C. in a microwave oven for 10 min.The reaction mixture was diluted with ethyl acetate (10 ml), washed withhydrochloric acid (1M, 5 ml), saturated sodium carbonate (5 ml) andbrine (5 ml). The organic phase was dried (magnesium sulfate) andconcentrated under vacuum. The residue was purified using an SPEcartridge (silica) eluting with a cyclohexane/ethyl acetate gradient togive the title compound as a pale yellow solid (135 mg).

LC-MS: Rt 3.87 min, MH+464, 466.

General Method 2

A mixture of3-[1-(4-bromophenyl)-1H-indazol-5-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide(Example 29, 1 eq), amine (1.2 eq) and sodium tert-butoxide (4.5 eq) wastreated with a solution of tris(dibenzylideneacetone)dipalladium (0.015eq) and tri-t-butylphosphoniumtetrafluoroborate (0.3 eq) in dry DME (10ml/eq) then heated at 125° C. for 18 h. The solvent was evaporated andthe residue was partitioned between ethyl acetate and water. Isolationof the crude product from the organic layer was followed by purificationon an acidic ion-exchange column (SCX) and/or preparative HPLC.

Example 303-(1-{4-[(Cyclohexylmethyl)amino]phenyl}-1H-indazol-5-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide,formate salt

The title compound was prepared by General Method 2 usingcyclohexylmethylamine (12 mg) to give a brown oil (7 mg).

LC-MS: Rt 4.16 min, MH+497.

Example 31N-Cyclopropyl-3-[1-(4-{[2-(dimethylamino)ethyl]amino}phenyl)-1H-indazol-5-yl]-5-fluoro-4-methylbenzamide,diformate salt

The title compound was prepared by General Method 2 usingN,N-dimethylethylenediamine (0.014 ml) to give a white solid (20 mg).

LC-MS: Rt 2.64 min, MH+472.

Example 32N-Cyclopropyl-3-fluoro-4-methyl-5-{1-[4-(tetrahydro-2H-pyran-4-ylamino)phenyl]-1H-indazol-5-yl}benzamide,formate salt

The title compound was prepared by General Method 2 usingtetrahydro-2H-pyran-4-ylamine (20 mg) to give a brown solid (18 mg).

LC-MS: Rt 3.40 min, MH+485.

Example 33N-Cyclopropyl-3-fluoro-4-methyl-5-(1-{4-[(tetrahydro-2-furanylmethyl)amino]phenyl}-1H-indazol-5-yl)benzamide,formate salt

The title compound was prepared by General Method 2 using(tetrahydro-2-furanylmethyl)amine (0.014 ml) to give a brown glass (12mg).

LC-MS: Rt 3.56 min, MH+485.

Example 34N-Cyclopropyl-3-fluoro-4-methyl-5-[1-(4-{[2-(methyloxy)ethyl]amino}phenyl)-1H-indazol-5-yl]benzamide,formate salt

The title compound was prepared by General Method 2 using2-methoxyethylamine (0.011 ml) to give a brown glass (15 mg).

LC-MS: Rt 3.40 min, MH+459.

Example 35N-Cyclopropyl-3-[1-(4-{[3-(dimethylamino)propyl]amino}phenyl)-1H-indazol-5-yl]-5-fluoro-4-methylbenzamide,diformate salt

The title compound was prepared by General Method 2 usingN,N-dimethyl-1,3-propanediamine (0.016 ml) to give a brown glass (10mg).

LC-MS: Rt 2.67 min, MH+486.

Example 36(±)-N-Cyclopropyl-3-(1-{4-[(2,3-dihydroxypropyl)amino]phenyl}-1H-indazol-5-yl)-5-fluoro-4-methylbenzamide

The title compound was prepared by General Method 2 using[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]amine (0.025 ml) to give anoff-white solid (14.6 mg).

LC-MS: Rt 3.03 min, MH+475.

Example 37N-Cyclopropyl-3-[1-(2,6-dimethyl-4-pyrimidinyl)-1H-indazol-5-yl]-5-fluoro-4-methylbenzamide

N-Cyclopropyl-4′,5-difluoro-3′-formyl-6-methyl-3-biphenylcarboxamide(Intermediate 16, 37 mg) and 4-hydrazino-2,6-dimethylpyrimidine (20 mg)were stirred together in acetonitrile (5 ml) for 2 h and then at 50° C.for 42 h. The solvent was evaporated and the residue was dissolved inDMSO (5 ml). Cesium carbonate (41.5 mg) was added and the mixture washeated at 180° C. in a microwave oven for 20 min. The solution wasdiluted with ethyl acetate (20 ml) then extracted with hydrochloric acid(0.5M, 3×20 ml). The combined acid fractions were basified to pH8 andextracted with chloroform (3×20 ml). The chloroform extracts werereduced to dryness under vacuum and the residue was purified bypreparative HPLC to give the title compound as a yellow glass (3.7 g).

LC-MS: Rt 2.42 min, MH+416.

Example 38N-Cyclopropyl-3-fluoro-4-methyl-5-[1-(6-oxo-1,6-dihydro-4-pyrimidinyl)-1H-indazol-5-yl]benzamide

N-Cyclopropyl-4′,5-difluoro-3′-formyl-6-methyl-3-biphenylcarboxamide(Intermediate 16, 40 mg) and 6-hydrazino-4(1H)-pyrimidinone (24 mg) weremixed in acetonitrile (5 ml) and stirred at 60° C. for 18 h. The solventwas evaporated and the residue was dissolved in DMSO (5 ml). Cesiumcarbonate (49.5 mg) was added and the mixture was heated at 180° C. in amicrowave oven for 15 min. The reaction mixture was diluted withchloroform/ethyl acetate (1:1, 10 ml), washed with water (2×10 ml) andbrine (1×10 ml) then concentrated under vacuum to give the titlecompound as a yellow solid (32 mg).

LC-MS: Rt 3.05 min, MH+404.

Example 39N-Cyclopropyl-3-fluoro-4-methyl-5-{3-[4-(methyloxy)phenyl]-1,2-benzisoxazol-6-yl}benzamide

A suspension of 6-bromo-3-[4-(methyloxy)phenyl]-1,2-benzisoxazole (30mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronicacid (28 mg), tetrakis(triphenylphosphine)palladium(0) (1 mg) andsaturated aqueous sodium hydrogen carbonate (0.25 ml) in isopropanol (1ml) was stirred at reflux under nitrogen for 6 h. The isopropanol wasremoved under vacuum and the residue was partitioned betweendichloromethane (3 ml) and water (3 ml). The organic layer was separatedusing a hydrophobic filter tube, the solvent was evaporated and theresidue was purified on an SPE cartridge (silica, 1 g) eluting withcyclohexane/ethyl acetate (100:0 to 80:20) to give the title compound asa crunchy yellow foam (26 mg).

LC-MS: Rt 3.68 min, MH+417.

Example 40N-Cyclopropyl-3-fluoro-5-[3-(4-hydroxyphenyl)-1,2-benzisoxazol-6-yl]-4-methylbenzamide

The procedure for Example 39 was followed using4-(6-bromo-1,2-benzisoxazol-3-yl)phenol (60 mg),{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (52mg), tetrakis(triphenylphosphine)palladium(0) (2 mg) and saturatedaqueous sodium hydrogen carbonate (0.5 ml) in isopropanol (2 ml).Elution of the SPE cartridge (silica, 2 g) with dichloromethane/methanol(100:0 to 98:2) gave an impure white solid (67 mg) which wasrecrystallised from isopropanol to give the title compound as acrystalline white solid (35 mg).

LC-MS: Rt 3.52 min, MH+403.

Example 41N-Cyclopropyl-3-fluoro-4-methyl-5-[1-(3-pyridinylmethyl)-1H-indazol-5-yl]benzamide

The procedure for Example 4 was followed usingN-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide(Intermediate 5, 70 mg), sodium hydride (60% dispersion in mineral oil,22 mg), 3-(bromomethyl)pyridine hydrobromide (63 mg) and DMF (5 ml) togive the title compound as a colourless glass (12 mg).

LC-MS: Rt 2.80 min, MH+401.

Example 42N-Cyclopropyl-3-fluoro-4-methyl-5-[1-(4-pyridinylmethyl)-1H-indazol-5-yl]benzamide

The procedure for Example 4 was followed usingN-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide(Intermediate 5, 70 mg), sodium hydride (60% dispersion in mineral oil,22 mg), 4-(bromomethyl)pyridine hydrobromide (63 mg) and DMF (5 ml) togive the title compound as a colourless glass (11 mg).

LC-MS: Rt 2.92 min, MH+401.

Example 43N-Cyclopropyl-3-fluoro-4-methyl-5-{1-[(1-oxido-2-pyridinyl)methyl]-1H-indazol-5-yl}benzamide

A solution ofN-cyclopropyl-3-fluoro-4-methyl-5-[1-(2-pyridinylmethyl)-1H-indazol-5-yl]benzamide(Example 8, 7 mg) in chloroform (1.6 ml) was treated with m-CPBA (5.2mg) then stirred at 60° C. for 1 h. Methanol (5 ml) was added and thesolution was applied to an Isolute amino cartridge. Elution withmethanol gave the title compound as a white solid (8 mg).

LC-MS: Rt 2.77 min, MH+417.

Example 44N-Cyclopropyl-3-fluoro-4-methyl-5-{1-[(1-oxido-3-pyridinyl)methyl]-1H-indazol-5-yl}benzamide

The procedure for Example 43 was followed usingN-cyclopropyl-3-fluoro-4-methyl-5-[1-(3-pyridinylmethyl)-1H-indazol-5-yl]benzamide(Example 41, 7 mg) m-CPBA (5.2 mg) and chloroform (3 ml) to give thetitle compound as a white solid (7 mg).

LC-MS: Rt 2.67 min, MH+417.

Example 45N-Cyclopropyl-3-fluoro-4-methyl-5-{1-[(1-oxido-4-pyridinyl)methyl]-1H-indazol-5-yl}benzamide

The procedure for Example 43 was followed usingN-cyclopropyl-3-fluoro-4-methyl-5-[1-(3-pyridinylmethyl)-1H-indazol-5-yl]benzamide(Example 42, 8 mg) m-CPBA (5.9 mg) and chloroform (2 ml) to give thetitle compound as a white solid (8 mg).

LC-MS: Rt 2.66 min, MH+417.

General Method 3

A mixture of 3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzoic acid(Intermediate 9, 224 mg) in thionyl chloride (7.5 ml) was stirred atreflux for 3 h. Excess thionyl chloride was removed under vacuum and theresidue was a zeotroped with toluene to remove residual thionylchloride. The crude acid chloride (187 mg) was dissolved in chloroform(10 ml) and an aliquot (1.0 ml) was added to a solution of theappropriate amine (100 μmol) in a mixture (0.5 ml) prepared by theaddition of diisopropylethylamine (69 μl), and dimethylaminopyridine (6mg) to DMF (20 ml). The resulting mixture was left at room temperaturefor 16 h, diisopropylethylamine (12 μl) was added and the mixture washeated at 50° C. for 24 h under nitrogen The resulting gums werepurified by preparative HPLC.

Example 46 3-Fluoro-4-methyl-5-(1phenyl-1H-indazol-5-yl)-N-2-pyrimidinylbenzamide

The title compound (1.3 mg) was prepared by General Method 3 using2-aminopyrimidine.

LC-MS: Rt 3.40 min, MH+424.

Example 473-Fluoro-N-(4-fluorophenyl)-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide

The title compound (4.1 mg) was prepared by General Method 3 using4-fluoroaniline.

LC-MS: Rt 4.0 min, MH+440.

Example 483-Fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)-N-3-pyridazinylbenzamide

The title compound (3.1 mg) was prepared by General Method 3 using2-aminopyridazine.

LC-MS: Rt 3.58 min, MH+424.

Example 493-Fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)-N-1H-pyrazol-3-ylbenzamide

The title compound (2.9 mg) was prepared by General Method 3 using3-aminopyrazole.

LC-MC: 4.10 min, MH+412.

Example 50N-(4-Fluorophenyl)-4-methyl-3-(1-phenyl-1H-indazol-5-yl)benzamide

A mixture of 5-bromo-1-phenyl-1H-indazole (Intermediate 1, 39 mg),N-cyclobutyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 23, 50 mg), tetrakis(triphenylphoshine)palladium (0) (3mg) and 2M aqueous sodium bicarbonate in isopropanol (1 ml) was heatedat 150° C. for 10 min in a microwave oven. The reaction mixture wasapplied to an SPE cartridge (silica, 50 g) and eluted with acyclohexane/ethyl acetate gradient (100:0 to 0:100) to give the titlecompound as a white solid (40 mg).

LC-MS: Rt 3.80 min, MH+422.

Example 51N-Ethyl-3-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide

A mixture of 6-bromo-3-(4-fluorophenyl)-1H-indazole (Intermediate 20, 27mg),N-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 18, 29 mg), tetrakis(triphenylphosphine)palladium(0) (2mg) and aqueous sodium hydrogen carbonate (1M, 1 ml) in isopropanol (2ml) was stirred in a microwave oven at 150° C. for 15 min. Water andchloroform were added and the organic layer was separated using ahydrophobic filter tube. The solvent was evaporated and the residue waspurified on an SPE cartridge (silica, 2 g) eluting withcyclohexane/ethyl acetate (100:0 to 50:50) to give the title compound(21 mg).

LC-MS: Rt 3.40 min, MH+374.

Example 52N-Cyclopropyl-3-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide

The procedure for Example 51 was followed using6-bromo-3-(4-fluorophenyl)-1H-indazole (Intermediate 20, 27 mg),N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(30 mg), tetrakis(triphenylphosphine)palladium(0) (2 mg) and aqueoussodium hydrogen carbonate (1M, 1 ml) in isopropanol (2 ml) to give thetitle compound (20 mg).

LC-MS: Rt 3.3 min, MH+386.

Example 53N-Ethyl-4-methyl-3-{3-[4-(methyloxy)phenyl]-1H-indazol-6-yl}benzamide

The procedure for Example 51 was followed using6-bromo-3-(4-methoxyphenyl)-1H-indazole (Intermediate 22, 23 mg),N-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 18, 30 mg), tetrakis(triphenylphosphine)palladium(0) (2mg) and aqueous sodium hydrogen carbonate (1M, 1 ml) in isopropanol (2ml) to give the title compound (18 mg).

LC-MS: Rt 3.41 min, MH+386.

Example 54N-Cyclopropyl-4-methyl-3-{3-[4-(methyloxy)phenyl]-1H-indazol-6-yl}benzamide

The procedure for Example 51 was followed using6-bromo-3-(4-methoxyphenyl)-1H-indazole (Intermediate 22, 23 mg),N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(30 mg), tetrakis(triphenylphosphine)palladium(0) (2 mg) and aqueoussodium hydrogen carbonate (1M, 1 ml) in isopropanol (2 ml) to give thetitle compound (22 mg).

LC-MS: Rt 3.32 min, MH+398.

Example 55N-Ethyl-3-[3-(6-fluoro-3-pyridinyl)-1H-indazol-6-yl]-4-methylbenzamide

A stirred mixture ofN-ethyl-3-(3-iodo-1H-indazol-6-yl)-4-methylbenzamide (Intermediate 24,30 mg), (6-fluoro-3-pyridinyl)boronic acid (130 mg),tetrakis(triphenylphosphine)palladium(0) (5 mg) and aqueous sodiumhydrogen carbonate (1M, 0.3 ml) in isopropanol (1.5 ml) was heated at150° C. in a microwave oven for 15 min. The solvent was removed undervacuum and the residue was purified by preparative HPLC to give thetitle compound as a pale brown solid (12 mg).

LC-MS: Rt 3.29 min, MH⁺375.

Example 56N-Ethyl-3-{3-[4-(ethyloxy)phenyl]-1H-indazol-6-yl}-4-ethylbenzamide

The procedure for Example 55 was followed usingN-ethyl-3-(3-iodo-1H-indazol-6-yl)-4-methylbenzamide (Intermediate 24,33 mg), (4-ethoxyphenyl)boronic acid (16 mg),tetrakis(triphenylphosphine)palladium(0) (2 mg) and aqueous sodiumhydrogen carbonate (1M, 0.2 ml) in isopropanol (1 ml) to give the titlecompound (16 mg).

LC-MS: 3.59 min, MH⁺400.

Example 57N-Ethyl-4-methyl-3-{3-[4-(methylsulfonyl)phenyl]-1H-indazol-6-yl}benzamide

The procedure for Example 55 was followed usingN-ethyl-3-(3-iodo-1H-indazol-6-yl)-4-methylbenzamide (Intermediate 24,33 mg) [4-(methylsulfonyl)phenyl]-boronic acid (19 mg)tetrakis(triphenylphosphine)palladium(0) (2 mg) and aqueous sodiumhydrogen carbonate (1M, 0.2 ml) in isopropanol (1 ml) to give the titlecompound (16 mg).

LC-MS: 3.07 min, MH⁺434.

Example 58N-Ethyl-3-fluoro-4-methyl-5-[3-(4-methylphenyl)-1H-indazol-6-yl]benzamide

A mixture ofN-ethyl-3-fluoro-5-(3-iodo-1H-indazol-6-yl)-4-methylbenzamide(Intermediate 28, 0.192 g), tetrakis(triphenylphosphine)palladium (16mg) and aqueous sodium hydrogen carbonate (1M, 0.1 ml) was suspended inisopropanol (1.8 ml). An aliquot (0.2 ml) was added to(4-methylphenyl)boronic acid (8.5 mg) and the mixture was heated bymicrowave in a sealed vessel at 150° C. for 10 min. The solvent wasevaporated and the residue was purified by preparative HPLC to give thetitle compound as a colourless glass (10 mg).

LCMS: Rt 3.59 min, MH+388.

Example 59N-Ethyl-3-fluoro-4-methyl-5-{3-[4-(trifluoromethyl)phenyl]-1H-indazol-6-yl}benzamide

The procedure for Example 58 was followed using an aliquot (0.2 ml) ofthe N-ethyl-3-fluoro-5-(3-iodo-1H-indazol-6-yl)-4-methylbenzamide(Intermediate 28) and tetrakis(triphenylphosphine)palladium inpropan-2-ol mixture, [4-(trifluoromethyl)phenyl]boronic acid (12 mg) andsodium hydrogen carbonate solution (1M, 0.1 ml) to give the titlecompound as a colourless glass (7.1 mg).

LCMS: Rt 3.79 min, MH+442.

Example 603-[3-(4-Chlorophenyl)-1H-indazol-6-yl]-N-ethyl-5-fluoro-4-methylbenzamide

The procedure for Example 58 was followed using an aliquot (0.2 ml) ofthe N-ethyl-3-fluoro-5-(3-iodo-1H-indazol-6-yl)-4-methylbenzamide(Intermediate 28) and tetrakis(triphenylphosphine)palladium inpropan-2-ol mixture, [4(4-chlorophenyl)boronic acid (12 mg) and sodiumhydrogen carbonate solution (1M, 0.1 ml) to give the title compound as acolourless glass 8.4 mg).

LCMS: Rt 3.72 min, MH+408.

Example 61N-Ethyl-3-fluoro-4-methyl-5-{3-[6-(methyloxy)-3-pyridinyl]-1H-indazol-6-yl}benzamide

A mixture of 6-bromo-3-[6-(methyloxy)-3-pyridinyl]-1H-indazole(Intermediate 30, 59 mg),N-ethyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 31, 71 mg), tetrakis(triphenylphosphine)palladium(0) (10mg) and aqueous sodium hydrogen carbonate (1M, 2.5 ml) in isopropanol(2.5 ml) in a sealed vessel was heated at 150° C. for 15 min in amicrowave oven. The reaction mixture was partitioned between chloroformand water and the organic layer was separated using a hydrophobic filtertube The solvent was evaporated and the residue was and purified bypreparative HPLC to give the title compound (32 mg).

LC-MS: Rt 3.3 min, MH⁺405.

Example 62N-Ethyl-3-fluoro-4-methyl-5-[3-(2-pyridinyl)-1H-indazol-6-yl]benzamide

A mixture of 6-bromo-3-(2-pyridinyl)-1H-indazole (Intermediate 33, 74mg),N-ethyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 31, 98 mg), tetrakis(triphenylphosphine)palladium(0) (10mg) and aqueous sodium hydrogen carbonate (1M, 2.5 ml) in 2-propanol(2.5 ml) in a sealed vessel was heated at 150° C. for 15 min in amicrowave oven. The reaction mixture was partitioned between chloroformand water and the organic layer separated using a hydrophobic filtertube. The solvent was evaporated and the residue was purified bypreparative HPLC to give the title compound (5 mg).

LC-MS: Rt 3.4 min, MH⁺374.

Example 63N-Ethyl-3-fluoro-4-methyl-5-[3-(1-oxido-2-pyridinyl)-1H-indazol-6-yl]benzamide

A solution ofN-ethyl-3-fluoro-4-methyl-5-[3-(2-pyridinyl)-1H-indazol-6-yl]benzamide(Example 62, 15 mg) in chloroform (1 ml) was treated with3-chloroperoxybenzoic acid (14 mg) then stirred for 2 h. Methanol wasadded and the solution was applied to an Isolute amino cartridge,eluting with methanol. The solvent was evaporated and the residue waspurified by preparative HPLC to give the title compound (0.6 mg).

LC-MS: Rt 2.70 min, MH⁺391.

Example 64N-(1-Ethyl-1H-pyrazol-5-yl)-3-fluoro-5-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide

A mixture ofN-(1-ethyl-1H-pyrazol-5-yl)-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(48 mg), 6-bromo-3-(4-fluorophenyl)-1H-indazole (43 mg) aqueous sodiumhydrogen carbonate (1M, 0.3 ml) andtetrakis(triphenylphosphine)palladium (4.8 mg) in isopropanol (1.5 ml)in a sealed vessel was heated at 150° C. for 15 min in a microwave oven.The solvent was evaporated and the residue was purified by preparativeHPLC to give the title compound as a colourless glass (22 mg).

LC-MS: Rt 3.60 min, MH⁺458.

Example 653-[3-(1,3-Dimethyl-1H-pyrazol-5-yl)-1H-indazol-6-yl]-N-ethyl-4-methylbenzamide

A mixture of 6-bromo-3-(1,3-dimethyl-1H-pyrazol-5-yl)-1H-indazole(Intermediate 38, 34 mg),N-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 18, 34 mg), aqueous sodium hydrogen carbonate (1M, 234 μL)and tetrakis(triphenylphosphine)palladium(0) (3 mg) in propan-2-ol (2.5ml) was stirred in a sealed vial at 150° C. for 20 min in a microwaveoven. The solvent was removed under vacuum and the residue was purifiedby preparative HPLC to give the title compound as a white solid (8 mg).

LC-MS: Rt 3.1 min, MH+374.

Example 663-Fluoro-5-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide

A mixture of3-fluoro-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 40, 50 mg), 6-bromo-3-(4-fluorophenyl)-1H-indazole(Intermediate 20, 41 mg), aqueous sodium hydrogen carbonate (1M, 0.28ml) and tetrakis(triphenylphosphine)palladium (8 mg) in isopropanol (1ml) in a sealed vial was heated at 150° C. for 15 min in a microwaveoven. The solvent was evaporated and the residue was purified bypreparative HPLC to give the title compound as a white solid (25 mg).

LCMS: Rt 3.48 min, MH+444.

Example 673-Fluoro-5-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methyl-N-1H-pyrazol-3-ylbenzamide

A mixture of3-fluoro-4-methyl-N-1H-pyrazol-5-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 42, 47 mg), 6-bromo-3-(4-fluorophenyl)-1H-indazole(Intermediate 20, 41 mg), aqueous sodium hydrogen carbonate (1M, 0.28ml) and tetrakis(triphenylphosphine)palladium (8 mg) in isopropanol (1.5ml) in a sealed vial was heated at 150° C. for 15 min in a microwaveoven. The solvent was evaporated and the residue was purified bypreparative HPLC to give the title compound as a white solid (25 mg).

LCMS: Rt 3.56 min, MH+430.

Example 68N-Ethyl-4-methyl-3-{3-[6-(4-morpholinyl)-3-pyridinyl]-1H-indazol-6-yl}benzamide

A mixture of 6-bromo-3-[6-(4-morpholinyl)-3-pyridinyl]-1H-indazole(Intermediate 45, 70 mg),N-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 18, 56 mg), aqueous sodium hydrogen carbonate (1M, 390 μL)and tetrakis(triphenylphosphine)palladium(0) (4.5 mg) in isopropanol(2.5 ml) in a sealed vial was stirred at 150° C. for 20 min in amicrowave oven. The solvent was removed under vacuum and the residue waspurified by preparative HPLC to give the title compound as a yellowsolid (5 mg).

LC-MS: Rt 2.95 min, MS+442.

Example 69N-Ethyl-3-fluoro-4-methyl-5-[3-(2-pyrimidinyl)-1H-indazol-6-yl]benzamide

The procedure for Example 68 was followed using6-bromo-3-(2-pyrimidinyl)-1H-indazole (Intermediate 48, 17 mg),N-ethyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 31, 19 mg), sodium hydrogen carbonate (1M, 124 μL) andtetrakis(triphenylphosphine)palladium(0) (1.4 mg) in isopropanol (2.5ml) to give the title compound (1.7 mg).

LC-MS: Rt 3.05 min, MS+376.

Example 70N-Ethyl-4-methyl-5-[3-(5-pyrimidinyl)-1H-indazol-6-yl]benzamide

A mixture of 6-bromo-3-(5-pyrimidinyl)-1H-indazole (Intermediate 51, 60mg),N-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 18, 63 mg), aqueous sodium hydrogen carbonate (1M, 436 μL)and tetrakis(triphenylphosphine)palladium(0) (5 mg) in isopropanol (4ml) in a sealed vessel was stirred at 150° C. for 20 min in a microwaveoven. The solvent was removed under vacuum and the residue was purifiedby preparative HPLC to give the title compound (22 mg).

LC-MS: Rt 2.70 min, MS+358.

Example 71 N-Ethyl-4-methyl-3-[3-(2-pyrazinyl)-1H-indazol-6-yl]benzamide

A mixture of 6-bromo-3-(2-pyrazinyl)-1H-indazole (Intermediate 54, 65mg),N-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 18, 68 mg), aqueous sodium hydrogen carbonate (1M, 472 μL)and PdCl₂(dppf) (10 mg) in isopropanol (5 ml) in a sealed vial wasstirred at 150° C. for 25 min in a microwave oven. More PdCl₂(dppf) (10mg) was added and the reaction mixture was heated for a further 25 minat 150° C. in the microwave oven. The solvent was removed under vacuumand the residue was purified by preparative HPLC to give the titlecompound as a brown solid (6 mg).

LC-MS: Rt 2.99 min, MS+358.

Example 72N-Ethyl-3-fluoro-5-{3-[4-fluoro-2-(methyloxy)phenyl]-1H-indazol-6-yl}-4-methylbenzamide

A mixture of3-(3-bromo-1H-indazol-6-yl)-N-ethyl-5-fluoro-4-methylbenzamide(Intermediate 55, 50 mg), [4-fluoro-2-(methyloxy)phenyl]boronic acid (27mg), tetrakis(triphenylphosphine)palladium(0) (2 mg) and aqueous sodiumhydrogen carbonate (0.125 ml) in isopropanol (0.5 ml) in a sealed vialwas stirred at 150° C. for 20 min in a microwave oven. Water (2 ml) anddichloromethane (2 ml) were added, the phases were separated using ahydrophobic filter tube and the aqueous layer was washed with moredichloromethane (4 ml). The combined organics were concentrated undervacuum and the residue was purified by preparative HPLC to give thetitle compound (29 mg).

LC-MS: Rt 3.5 min, MH+422.

Example 73N-Ethyl-3-fluoro-4-methyl-5-{3-[2-(methyloxy)-3-pyridinyl]-1H-indazol-6-yl}benzamide

The procedure for Example 72 was followed using3-(3-bromo-1H-indazol-6-yl)-N-ethyl-5-fluoro-4-methylbenzamide(Intermediate 55, 50 mg) [2-(methyloxy)-3-pyridinyl]boronic acid (24 mg)tetrakis(triphenylphosphine)palladium(0) (2 mg) and aqueous sodiumhydrogen carbonate (0.125 ml) in isopropanol (0.5 ml) to give the titlecompound (22 mg).

LC-MS: Rt 3.1 min, MH+405.

Example 74N-Ethyl-3-fluoro-5-[3-(4-fluoro-2-methylphenyl)-1H-indazol-6-yl]-4-methylbenzamide

The procedure for Example 72 was followed using3-(3-bromo-1H-indazol-6-yl)-N-ethyl-5-fluoro-4-methylbenzamide(Intermediate 55, 50 mg) (4-fluoro-2-methylphenyl)boronic acid (31 mg)tetrakis(triphenylphosphine)palladium(0) (2 mg) and aqueous sodiumhydrogen carbonate (0.125 ml) in isopropanol (0.5 ml) to give the titlecompound (23 mg).

LC-MS: Rt 3.5 min, MH+406.

Example 75N-Ethyl-3-fluoro-4-methyl-5-[3-(3-pyridinyl)-1H-indazol-6-yl]benzamide

The procedure for Example 72 was followed using3-(3-bromo-1H-indazol-6-yl)-N-ethyl-5-fluoro-4-methylbenzamide(Intermediate 55, 50 mg) 3-pyridinylboronic acid (20 mg)tetrakis(triphenylphosphine)palladium(0) (2 mg) and aqueous sodiumhydrogen carbonate (0.125 ml) in isopropanol (0.5 ml). Moretetrakis(triphenylphosphine)palladium(0)(2 mg) was added and heating wascontinued for a further 20 min. A similar work-up and purification bypreparative HPLC gave the title compound (7.8 mg).

LC-MS: Rt 3.0 min, MH+375.

Example 763-[3-(3,5-Dimethyl-4-isoxazolyl)-1H-indazol-6-yl]-N-ethyl-5-fluoro-4-methylbenzamide

The procedure for Example 72 was followed using3-(3-bromo-1H-indazol-6-yl)-N-ethyl-5-fluoro-4-methylbenzamide(Intermediate 55, 50 mg), (3,5-dimethyl-4-isoxazolyl)boronic acid (22.5mg), tetrakis(triphenylphosphine)palladium(0) (2 mg) and aqueous sodiumhydrogen carbonate (0.125 ml) in isopropanol (0.5 ml). Heating wascontinued for a further 30 min and a similar work-up and purification bypreparative HPLC gave the title compound (6 mg).

LC-MS: Rt 3.2 min, MH+393.

Example 77N-Ethyl-6-(6-{5-[(ethylamino)carbonyl]-2-methylphenyl}-1H-indazol-3-yl)-3-pyridinecarboxamide

A mixture of impure 1,1-dimethylethyl 1,1-dimethylethyl2-({5′-[(ethylamino)carbonyl]-3-fluoro-2′-methyl-4-biphenylyl}{5-[(ethylamino)carbonyl]-2-pyridinyl}methylidene)hydrazinecarboxylate(Intermediate 59, 198 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (54 uL)in tetrahydrofuran (3 mL) in a sealed vial was heated at 150° C. for30mins in a microwave oven. The solvent was removed under vacuum and theresidue purified by chromatography on a silica column eluting with acyclohexane:ethyl acetate gradient. The resulting product was furtherpurified by preparative HPLC to give the title compound (3 mg).

LC-MS: Rt 2.91 min, MS+428.

Example 78N-(1,4-Dimethyl-1H-pyrazol-5-yl)-3-fluoro-5-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide

3-Fluoro-5-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzoic acid(Intermediate 60, 18 mg) in DMF (1 ml), 1-hydroxy-7-azabenzotriazole (1mg) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, hydrochloride(18.2 mg) were added to a solution of 1,4-dimethyl-1H-pyrazol-5-amine(12.2 mg) in DMF (1 ml) and the mixture was stirred at room temperatureovernight. The DMF was removed under a stream of nitrogen and theresidue was purified by preparative HPLC to give the title compound as awhite solid (5.4 mg).

LCMS: Rt 3.56 min, MH+458.

Example 79N-(1,4-Dimethyl-1H-pyrazol-5-yl)-3-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide

A mixture ofN-(1,4-dimethyl-1H-pyrazol-5-yl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 61, 42 mg), 6-bromo-3-(4-fluorophenyl)-1H-indazole(Intermediate 20, 33 mg) aqueous sodium hydrogen carbonate (1M, 0.25 ml)and tetrakis(triphenylphosphine)palladium (2.5 mg) in isopropanol (1.5ml) in a sealed vessel was heated in a microwave oven at 150° C. for 10min. The solvent was evaporated and the residue was purified bypreparative HPLC to give the title compound as a white foam (22.5 mg).

LCMS: Rt 3.50 min, MH+440.

Example 80N-(3,5-Dimethyl-4-isoxazolyl)-3-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide

A mixture ofN-(3,5-dimethyl-4-isoxazolyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 62, 34 mg), 6-bromo-3-(4-fluorophenyl)-1H-indazole(Intermediate 20, 29 mg), aqueous sodium hydrogen carbonate (1M, 0.2 ml)and tetrakis(triphenylphosphine)palladium (2 mg) in isopropanol (1.5 ml)in a sealed vessel was heated in a microwave oven at 150° C. for 10 min.The solvent was evaporated and the residue was purified by preparativeHPLC to give the title compound as an off-white solid (22.5 mg).

LCMS: Rt 3.43 min, MH+441.

Example 813-[3-(1,2-Dimethyl-1H-imidazol-5-yl)-1H-indazol-6-yl]-N-ethyl-5-fluoro-4-methylbenzamide

A solution of 1,1-dimethylethyl3-[3-(1,2-dimethyl-1H-imidazol-5-yl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indazol-6-yl]-5-fluoro-4-methylbenzoate(Intermediate 68, 90 mg), hydrochloric acid (5M, 7 ml) and acetonitrie(5 ml) was heated at 850 for 1 h. The solvent was evaporated and theresidue was triturated with ether (2×20 ml). The residual solid wastreated with thionyl chloride (4 ml) and toluene (5 ml) then heated atreflux for 40 min. The solvent was removed under vacuum and the residuewas suspended in THF (20 ml) and treated with a solution of ethylaminein THF (2M, 5 ml). The solvent was removed under vacuum and the residuewas purified by preparative HPLC to give the title compound as a palebrown solid (29 mg).

LC-MS: Rt 2.26 min, MH+392.

Example 82N-Ethyl-3-fluoro-4-methyl-5-[3-(2-methyl-4-pyridinyl)-1H-indazol-6-yl]benzamide,formate salt

A mixture of (2-methyl-4-pyridinyl)boronic acid hydrochloride (20 mg),3-(3-bromo-1H-indazol-6-yl)-N-ethyl-5-fluoro-4-methylbenzamide(Intermediate 55, 38 mg), sodium hydrogen carbonate (1.5 ml) andtetrakis(triphenylphosphine) palladium(0) (5 mg) in isopropanol (1 ml)in a sealed vessel was heated at 150° C. in a microwave oven for 15 min.The crude mixture was applied to an SCX cartridge (silica) and elutedwith 10% aqueous ammonia (0.88) in methanol. The solvent was evaporatedand the residue was purified by preparative HPLC to give the titlecompound (10.1 mg).

LC-MS: Rt 2.6 min MH+389.

ABBREVIATIONS

-   AcOH Acetic acid-   Ar Aryl-   Boc t-Butoxycarbonyl-   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene-   DCM Dichloromethane-   DIPEA N,N-Diisopropylethylamine-   DME 1,2-Dimethoxyethane-   DMF Dimethylformamide-   DMSO Dimethylsulfoxide-   EtOH Ethanol-   h Hours-   Hal Halogen-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   Het Heteroaryl-   m-CPBA 3-Chloroperbenzoic acid-   MeCN Acetonitrile-   MeOH Methanol-   min Minutes-   Ms Mesyl-   NBS N-Bromosuccinimide-   PdCl₂(dppf)    [1,1′-bis(Diphenylphosphino)ferrocene]dichloropalladium (II) complex    with dichloromethane (1:1)-   Rt Retention Time-   SPE Solid phase extraction-   THF Tetrahydrofuran

Biological Examples

The activity of compounds of formula (I) as p38 inhibitors may bedetermined by the following in vitro assays:

Fluorescence Anisotropy Kinase Binding Assay 1

The kinase enzyme, fluorescent ligand and a variable concentration oftest compound are incubated together to reach thermodynamic equilibriumunder conditions such that in the absence of test compound thefluorescent ligand is significantly (>50%) enzyme bound and in thepresence of a sufficient concentration (>10× K_(i)) of a potentinhibitor the anisotropy of the unbound fluorescent ligand is measurablydifferent from the bound value.

The concentration of kinase enzyme should preferably be ≧1× K_(f). Theconcentration of fluorescent ligand required will depend on theinstrumentation used, and the fluorescent and physicochemicalproperties. The concentration used must be lower than the concentrationof kinase enzyme, and preferably less than half the kinase enzymeconcentration. A typical protocol is:

All components dissolved in Buffer of final composition 62.5 mM HEPES,pH 7.5, 1.25 mM CHAPS, 1.25 mM DTT, 12.5 mM MgCl₂ 3.3% DMSO.

p38 Enzyme concentration: 12 nM

Fluorescent ligand concentration: 5 nM

Test compound concentration: 0.1 nM-100 μM

Components incubated in 30 μl final volume in NUNC 384 well blackmicrotitre plate until equilibrium reached (5-30 mins)

Fluorescence anisotropy read in LJL Acquest.

Definitions: K_(i)=dissociation constant for inhibitor binding

-   -   K_(f)=dissociation constant for fluorescent ligand binding

The fluorescent ligand is the following compound:

which is derived from5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-2-chlorophenoland rhodamine green.

Fluorescence Anisotropy Kinase Binding Assay 2 (Macro Volume Assay)

The kinase enzyme, fluorescent ligand and a variable concentration oftest compound are incubated together to reach thermodynamic equilibriumunder conditions such that in the absence of test compound thefluorescent ligand is significantly (>50%) enzyme bound and in thepresence of a sufficient concentration (>10× Ki) of a potent inhibitorthe anisotropy of the unbound fluorescent ligand is measurably differentfrom the bound value.

The concentration of kinase enzyme should preferably be 2× Kf. Theconcentration of fluorescent ligand required will depend on theinstrumentation used, and the fluorescent and physicochemicalproperties. The concentration used must be lower than the concentrationof kinase enzyme, and preferably less than half the kinase enzymeconcentration.

The fluorescent ligand is the following compound:

which is derived from5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-2-chlorophenoland rhodamine green.

Recombinant human p38α was expressed as a GST-tagged protein. Toactivate this protein, 3.5 μM unactivated p38α was incubated in 50 mMTris-HCl pH 7.5, 0.1 mM EGTA, 0.1% 2-mercaptoethanol, 0.1 mM sodiumvanadate, 10 mM MgAc, 0.1mM ATP with 200 nM MBP-MKK6 DD at 30 degreesfor 30 mins. Following activation p38% was re-purified and the activityassessed using a standard filter-binding assay.

Protocol: All components are dissolved in buffer of composition 62.5 mMHEPES, pH 7.5, 1.25 mM CHAPS, 1 mM DTT, 12.5 mM MgCl₂ with finalconcentrations of 12 nM p38α and 5 nM fluorescent ligand. 30 μl of thisreaction mixture is added to wells containing 1 μl of variousconcentrations of test compound (0.28 nM-16.6 μM final) or DMSO vehicle(3% final) in NUNC 384 well black microtitre plate and equilibrated for30-60 mins at room temperature. Fluorescence anisotropy is read inMolecular Devices Acquest (excitation 485 nm/emission 535 nm).

Definitions: Ki=dissociation constant for inhibitor binding

-   -   Kf=dissociation constant for fluorescent ligand binding

Fluorescence Anisotropy Kinase Binding Assay 3 (Micro Volume Assay)

The kinase enzyme, fluorescent ligand and a variable concentration oftest compound are incubated together to reach thermodynamic equilibriumunder conditions such that in the absence of test compound thefluorescent ligand is significantly (>50%) enzyme bound and in thepresence of a sufficient concentration (>10× Ki) of a potent inhibitorthe anisotropy of the unbound fluorescent ligand is measurably differentfrom the bound value.

The concentration of kinase enzyme should preferably be 2× Kf. Theconcentration of fluorescent ligand required will depend on theinstrumentation used, and the fluorescent and physicochemicalproperties. The concentration used must be lower than the concentrationof kinase enzyme, and preferably less than half the kinase enzymeconcentration.

The fluorescent ligand is the following compound:

which is derived from5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-2-chlorophenoland rhodamine green.

Recombinant human p38α was expressed as a GST-tagged protein. Toactivate this protein, 3.5 μM unactivated p38α was incubated in 50 mMTris-HCl pH 7.5, 0.1 mM EGTA, 0.1% 2-mercaptoethanol, 0.1 mM sodiumvanadate, 10 mM MgAc, 0.1 mM ATP with 200 nM MBP-MKK6 DD at 30 degreesfor 30 mins. Following activation p38α was re-purified and the activityassessed using a standard filter-binding assay.

Protocol: All components are dissolved in buffer of composition 62.5 mMHEPES, pH 7.5, 1.25 mM CHAPS, 1 mM DTT, 12.5 mM MgCl₂ with finalconcentrations of 12 nM p38α and 5 nM fluorescent ligand. 6 μl of thisreaction mixture is added to wells containing 0.2 μl of variousconcentrations of test compound (0.28 nM-16.6 μM final) or DMSO vehicle(3% final) in Greiner 384 well black low volume microtitre plate andequilibrated for 30-60 mins at room temperature. Fluorescence anisotropyis read in Molecular Devices Acquest (excitation 485 nm/emission 535nm).

Definitions: Ki=dissociation constant for inhibitor binding

-   -   Kf=dissociation constant for fluorescent ligand binding

Results

The compounds described in the Examples were tested in at least one ofthe assays described above and had either IC₅₀ values of <10 μM orpK_(i) values of >6.

1. A compound of formula (I):

wherein A is a fused 5-membered heteroaryl ring substituted by—(CH₂)_(m)aryl or —(CH₂)_(m)heteroaryl wherein the aryl or heteroaryl isoptionally substituted by one or more substituents independentlyselected from oxo, C₁₋₆alkyl, halogen, —CN, trifluoromethyl, —OR³,—(CH₂)_(n)CO₂R³, —NR³R⁴, —(CH₂)_(n)CONR³R⁴, —NHCOR³, —SO₂NR³R⁴, —NHSO₂R³and —S(O)_(p)R³, and A is optionally further substituted by onesubstituent selected from —OR⁵, halogen, trifluoromethyl, —CN, —CO₂R⁵and C₁₋₆alkyl optionally substituted by hydroxy; R¹ is selected frommethyl and chloro; R² is selected from —NH—CO—R⁶ and—CO—NH—(CH₂)_(q)—R⁷; R³ is selected from hydrogen,—(CH₂)_(r)—C₃₋₇cycloalkyl, —(CH₂)_(r)heterocyclyl, —(CH₂)_(r)aryl, andC₁₋₆alkyl optionally substituted by up to two substituents independentlyselected from —OR⁸ and —NR⁸R⁹, R⁴ is selected from hydrogen andC₁₋₆alkyl, or R³ and R⁴, together with the nitrogen atom to which theyare bound, form a 5- or 6-membered heterocyclic ring optionallycontaining one additional heteroatom selected from oxygen, sulfur andN—R¹⁰; R⁵ is selected from hydrogen and C₁₋₆alkyl; R⁶ is selected fromhydrogen, C₁₋₆alkyl, —(CH₂)_(q)—C₃₋₇cycloalkyl, trifluoromethyl,—(CH₂)_(s)heteroaryl optionally substituted by R¹¹ and/or R¹², and—(CH₂)_(s)phenyl optionally substituted by R¹¹ and/or R¹²; R⁷ isselected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, —CONHR¹³, phenyloptionally substituted by R¹¹ and/or R¹², and heteroaryl optionallysubstituted by R¹¹ and/or R¹²; R⁸ and R⁹ are each independently selectedfrom hydrogen and C₁₋₆alkyl; R¹⁰ is selected from hydrogen and methyl;R¹¹ is selected from C₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(q)—C₃₋₇cycloalkyl,—CONR¹³R¹⁴, —NHCOR¹⁴, halogen, —CN, —(CH₂)_(t)NR15R¹⁶, trifluoromethyl,phenyl optionally substituted by one or more R¹² groups, and heteroaryloptionally substituted by one or more R¹² groups; R¹² is selected fromC₁₋₆alkyl, C₁₋₆alkoxy, halogen, trifluoromethyl, and —(CH₂)_(t)NR¹⁵R¹⁶;R¹³ and R¹⁴ are each independently selected from hydrogen and C₁₋₆alkyl,or R¹³ and R¹⁴, together with the nitrogen atom to which they are bound,form a 5- or 6-membered heterocyclic ring optionally containing oneadditional heteroatom selected from oxygen, sulfur and N—R¹⁰, whereinthe ring may be substituted by up to two C₁₋₆alkyl groups; R¹⁵ isselected from hydrogen, C₁₋₆alkyl and —(CH₂)_(q)—C₃₋₇cycloalkyloptionally substituted by C₁₋₆alkyl, R¹⁶ is selected from hydrogen andC₁₋₆alkyl, or R¹⁵ and R¹⁶, together with the nitrogen atom to which theyare bound, form a 5- or 6-membered heterocyclic ring optionallycontaining one additional heteroatom selected from oxygen, sulfur andN—R¹⁰; X and Y are each independently selected from hydrogen, methyl andhalogen; m, n, p and q are each independently selected from 0, 1 and 2;r and s are each independently selected from 0 and 1; and t is selectedfrom 0, 1, 2 and 3; with the proviso that when A is substituted by—(CH₂)_(m)heteroaryl and m is 0, the —(CH₂)_(m)heteroaryl group is not a5-membered heteroaryl ring optionally substituted by C₁₋₂alkyl; or apharmaceutically acceptable derivative thereof.
 2. A compound accordingto claim 1 wherein A is a fused 5-membered heteroaryl ring containing upto two heteroatoms independently selected from oxygen and nitrogen.
 3. Acompound according to claim 1 or wherein R¹ is methyl.
 4. A compoundaccording to claim 1 wherein R² is —CO—NH—(CH₂)_(q)—R⁷.
 5. A compoundaccording to claim 1 wherein A is substituted by —(CH₂)_(m)heteroarylwherein the heteroaryl is a 5- or 6-membered heteroaryl ring containingup to two heteroatoms independently selected from oxygen and nitrogen.6. A compound according to claim 5 wherein the heteroaryl is optionallysubstituted by one or two substituents independently selected from oxo,C₁₋₆alkyl, halogen, —OR³, —NR³R⁴ and —(CH₂)_(n)CONR³R⁴.
 7. A compoundaccording to claim 6 wherein the heteroaryl is substituted by one or twosubstituents independently selected from oxo and C₁₋₆alkyl.
 8. Acompound according to claim 1 wherein A is substituted by —(CH₂)_(m)arylwherein the aryl is phenyl.
 9. A compound according to claim 8 whereinthe aryl is substituted by one or two substituents independentlyselected from C₁₋₆alkyl, halogen, —CN, trifluoromethyl, —OR³, —NR³R⁴,—(CH₂)_(n)CONR³R⁴ and —S(O)_(p)R³.
 10. A compound according to claim 1wherein X is hydrogen or fluorine.
 11. A compound according to claim 1substantially as hereinbefore defined with reference to any one ofExamples 1 to 82, or a pharmaceutically acceptable derivative thereof.12. A compound selected from:N-cyclopropyl-3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide;N-cyclopropyl-3-fluoro-5-[1-(4-fluorophenyl)-1H-indazol-5-yl]-4-methylbenzamide;N-cyclopropyl-3-fluoro-5-[1-(4-fluoro-2-methylphenyl)-1H-indazol-5-yl]-4-methylbenzamide;N-cyclopropyl-3-fluoro-4-methyl-5-{1-[4-(4-morpholinyl)phenyl]-1H-indazol-5-yl}benzamide;N-ethyl-3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide;N-(cyclopropylmethyl)-3-fluoro-4-methyl-5-(1-phenyl-1H-indazol-5-yl)benzamide;N-cyclopropyl-3-fluoro-4-methyl-5-{1-[4-(methylsulfonyl)phenyl]-1H-indazol-5-yl}benzamide;N-cyclopropyl-3-fluoro-4-methyl-5-(1-{4-[2-(methylamino)-2-oxoethyl]phenyl}-1H-indazol-5-yl)benzamide;N-cyclopropyl-3-[1-(4-{[2-(dimethylamino)ethyl]amino}phenyl)-1H-indazol-5-yl]-5-fluoro-4-methylbenzamide;N-cyclopropyl-3-fluoro-4-methyl-5-{1-[4-(tetrahydro-2H-pyran-4-ylamino)phenyl]-1H-indazol-5-yl}benzamide;N-cyclopropyl-3-fluoro-4-methyl-5-(1-{4-[(tetrahydro-2-furanylmethyl)amino]phenyl}-1H-indazol-5-yl)benzamide;N-cyclopropyl-3-(1-{4-[(2,3-dihydroxypropyl)amino]phenyl}-1H-indazol-5-yl)-5-fluoro-4-methylbenzamide;N-cyclopropyl-3-fluoro-4-methyl-5-{3-[4-(methyloxy)phenyl]-1,2-benzisoxazol-6-yl}benzamide;N-cyclopropyl-3-fluoro-5-[3-(4-hydroxyphenyl)-1,2-benzisoxazol-6-yl]-4-methylbenzamide;N-cyclopropyl-3-fluoro-4-methyl-5-{1-[(1-oxido-2-pyridinyl)methyl]-1H-indazol-5-yl}benzamide;N-ethyl-3-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide;N-cyclopropyl-3-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide;N-ethyl-4-methyl-3-{3-[4-(methyloxy)phenyl]-1H-indazol-6-yl}benzamide;N-cyclopropyl-4-methyl-3-{3-[4-(methyloxy)phenyl]-1H-indazol-6-yl}benzamide;N-(1-ethyl-1H-pyrazol-5-yl)-3-fluoro-5-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide;3-fluoro-5-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide;N-ethyl-3-fluoro-5-{3-[4-fluoro-2-(methyloxy)phenyl]-1H-indazol-6-yl}-4-methylbenzamide;N-(1,4-dimethyl-1H-pyrazol-5-yl)-3-fluoro-5-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide;andN-(1,4-dimethyl-1H-pyrazol-5-yl)-3-[3-(4-fluorophenyl)-1H-indazol-6-yl]-4-methylbenzamide;or a pharmaceutically acceptable derivative thereof.
 13. Apharmaceutical composition comprising at least one compound according toclaim 1, or a pharmaceutically acceptable derivative thereof, inassociation with one or more pharmaceutically acceptable excipients,diluents and/or carriers.
 14. (canceled)
 15. A compound according toclaim 1, or a pharmaceutically acceptable derivative thereof, for use inthe treatment or prophylaxis of a condition or disease state mediated byp38 kinase activity or mediated by cytokines produced by the activity ofp38 kinase.
 16. A method for treating a condition or disease statemediated by p38 kinase activity or mediated by cytokines produced by theactivity of p38 kinase comprising administering to a patient in needthereof a compound according to claim 1, or a pharmaceuticallyacceptable derivative thereof.
 17. (canceled)
 18. A process forpreparing a compound of formula (I) according to claim 1, or apharmaceutically acceptable derivative thereof, which comprises (a)reacting a compound of formula (II)

in which R¹, R², X and Y are as defined in claim 1 and A¹ is anunsubstituted fused 5-membered heteroaryl ring with a halide derivativeof formula (IIA) or (IIB)Z-(CH₂)_(m)aryl  (IIA)Z-(CH₂)_(m)heteroaryl  (IIB) in which —(CH₂)_(m)aryl and—(CH₂)_(m)heteroaryl are as defined in claim 1 and Z is halogen, in thepresence of a base, or, when A is substituted by —(CH₂)_(m)aryl whereinm is 0, reacting the compound of formula (II) with a boronic acidcompound of formula (IV)(HO)₂B—(CH₂)_(m)aryl  (IV) in which —(CH₂)_(m)aryl is as defined inclaim 1, (b) reacting a compound of formula (V)

in which A² is A as defined in claim 1 and Z¹ is halogen, with acompound of formula (VIA) or (VIB)

in which R¹, R², X and Y are as defined in claim 1, in the presence of acatalyst; (c) reacting a compound of formula (XVI)

in which A, R¹, X and Y are as defined in claim 1, with an aminecompound of formula (XV)R⁷—(CH₂)_(q)—NH₂  (XV) in which R⁷ and q are as defined in claim 1,under amide forming conditions; d) when A is a fused pyrazolyl, reactinga compound of formula (XVII)

in which R¹, R², X and Y are as defined in claim 1 and Z³ is halogen,with a hydrazine derivative of formula (VIIIA) or (VIIIB)H₂NNH—(CH₂)_(m)aryl  (VIIIA)H₂NNH—(CH₂)_(m)heteroaryl  (VIIIB) in which —(CH₂)_(m)aryl and—(CH₂)_(m)heteroaryl are as defined in claim 1; (e) reacting a compoundof formula (XVIII)

in which R¹, R², X and Y are as defined in claim 1 and A³ is a fused5-membered heteroaryl ring substituted by halogen, with a suitableboronic acid derivative; or (f) final stage modification of one compoundof formula (I) as defined in claim 1 to give another compound of formula(I) as defined in claim
 1. 19. A compound according to claim 2 whereinR¹ is methyl.
 20. A compound according to claim 2 wherein R² is—CO—NH—(CH₂)_(q)—R⁷.
 21. A compound according to claim 19 wherein R² is—CO—NH—(CH₂)_(q)—R⁷.
 22. A pharmaceutical composition comprising atleast one compound according to claim 12, or a pharmaceuticallyacceptable derivative thereof, in association with one or morepharmaceutically acceptable excipients, diluents and/or carriers.